FIELD OF INVENTION

The present invention relates to novel process for preparation of olmesartan medoxomil (I) substantially free of olmesartan acid impurity (II).

BACKGROUND OF THE INVENTION

Olmesartan medoxomil is chemically known as 4-(1 -hydroxy-1 -methylethyl)-2-propyl-1 -[[2'- (1 H-tetrazol-5-yl) [1 ,1 '-biphenyl]-4-yl]methyl]-1 H-imidazole-5-carboxylic acid (5-methyl-2- oxo-1 ,3-dioxol-4-yl)methyl ester and represented by formula I

(I)

Olmesaratan medoxomil (I) is a prodrug that is selective subtype angiotensin I I receptor antagonist and pharmaceutically used as an antihypertensive for the treatment and prophylaxis of hypertension.

Olmesartan medoxomil (I) was first disclosed in patent US 5,616,599, along with process for its preparation by treatment of trityl olmesartan medoxomil (III) with aqueous acetic acid. The filtrate obtained after removal of trityl alcohol was concentrated to give olmesartan medoxomil (I) containing about 4-5% of olmesartan acid impurity (II). This method is not industrially viable since, on a commercial scale the removal of large quantity of aqueous acetic acid would require longer durations causing higher rate of hydrolysis of olmesartan medoxomil (I) and producing excess of olmesartan acid impurity (II).

(III)

Another patent US 7,528,258 provides process for preparation of olmesartan medoxomil (I) wherein trityl olmesartan medoxomil (III) is contacted with sulphuric acid in a water miscible organic solvent. The trityl alcohol was filtered off, base was added to the filtrate and olmesartan medoxomil (I) with about 1 % of olmesartan acid impurity (II) was recovered. This method utilizes strong and corrosive acid like sulphuric acid and incorporate additional step of neutralizing the acid with a base.

Another application US 2008/0214637, describes process for preparation of olmesartan medoxomil (I), which involves reacting trityl olmesartan medoxomil (I II) with catalytic amount of acid selected from trifluoroacetic acid, methanesulphonic acid etc. The process further involves pH adjustment of the reaction mixture utilizing a base followed by multiple extractions and concentration of solvents and thereafter recovery of product by crystallization/precipitation.

PCT application WO 2010/067913 describes process for preparation of olmesartan medoxomil (I) from trityl olmesartan (III), wherein the triphenylmethane group is removed by using an acidic cation exchange resin. This process involves resin which is pre-treated with acid and after the reaction the resin is filtered and the filtrate concentrated, the product is recovered by crystallization. This process involves additional steps like treating the resin with an acid, filtrations, recovery of the resin etc.

Patent applications US 2006/00741 17 and US 2010/0076200 describes purification process to produce olmesartan medoxomil (I) containing less than 0.05% of olmesartan acid impurity (II), by crystallization from C ₃ -e ketone-water mixture. However, this process utilizes excess volumes of solvents.

Thus, there exists a need for improved process for preparation of olmesartan medoxomil (I) that can avoid use of strong acid, multiple steps, laborious work-up, large excess of solvent volumes etc.

SUMMARY OF THE INVENTION

The present invention provides novel process for preparation of olmesartan medoxomil (I) substantially free of olmesartan acid impurity (II) comprising, reacting trityl olmesartan medoxomil (III) with an acid, filtering the precipitate of trityl alcohol, subjecting the filtrate to agitated thin film drying, recovering olmesartan medoxomil (I) and optionally crystallizing olmesartan medoxomil (I) from an organic solvent.

DETAILED DESCRIPTION OF THE INVENTION

In a preferred embodiment, the present invention provides novel process for preparation of olmesartan medoxomil (I) comprising: a) reacting trityl olmesartan medoxomil (III) with an acid,

b) filtering the precipitate of trityl alcohol,

c) subjecting the filtrate to agitated thin film drying, and

d) recovering olmesartan medoxomil (I). In another embodiment, the present invention provides novel process for preparation of olmesartan medoxomil (I) substantially free of olmesartan acid impurity (II) comprising: a) reacting trityl olmesartan medoxomil (III) with an acid,

b) filtering the precipitate of trityl alcohol,

c) subjecting the filtrate to agitated thin film drying,

d) recovering olmesartan medoxomil (I), and

e) optionally crystallizing olmesartan medoxomil (I) from an organic solvent.

Olmesartan medoxomil (I) substantially free of olmesartan acid impurity (II) refers to compound (I) with less than 1 %, preferably less than 0.5%, more preferably less than 0.1 %, area percentage of HPLC of compound (II).

In the present invention, acid is selected from acetic acid, propionic acid, trifluoroacetic acid, hydrochloride acid etc., preferably acetic acid. Reaction of Step (a) is carried out in solvent selected from methanol, ethanol, acetone, ethyl acetate, tetrahydrofuran, 1 ,4- dioxane, water and mixtures thereof, preferably water. The reaction is carried out at a temperature of 0-100 °C, preferably 20-60 °C, more preferably 40-45 °C.

The filtrate is subjected to evaporation in agitated thin film dryer (ATFD) under vacuum. The feed rate of the filtrate is maintained at 4 to 10 ml per minute. The heating medium is jacketed hot water of temperature of 40-90 °C, preferably 45-50 °C. The vacuum was maintained at 20-100 mm/Hg, preferably 70-75 mm/Hg.

The olmesartan medoxomil (I) was crystallized from an organic solvent selected from acetone, acetonitrile, ethyl acetate and mixtures thereof.

By using the present process olmesartan medoxomil (I) substantially free of olmesartan acid impurity (II) can be obtained since the process avoids distillation of the reaction mixture to remove aqueous acid unlike the prior art method. The patent US 5,616,599 provides process in which the aqueous acetic acid is removed by concentration under reduced pressure, moreover to remove the traces of acetic acid and water, toluene is added and further concentrated. In this method the acidic reaction mixture is exposed to heat for longer duration causing hydrolysis of the product (I), therefore olmesartan medoxomil (I) obtained contains olmesartan acid impurity (II) in the range of 4-5 area percentage of HPLC.

During agitated thin film drying the aqueous organic acid is removed at a low temperature which avoids hydrolysis of olmesartan medoxomil (I) and results in olmesartan medoxomil (I) that is substantially free of olmesartan acid impurity (II).

The manufacture of olmesartan medoxomil (II) as per the process of present invention, has the following advantages over the prior art methods: a. Process does not utilize strong and corrosive acids like sulphuric acid,

b. Process avoids multiple steps like pH adjustment, extractions and concentration of solvents etc,

c. Avoids use of resin and the multiple operating parameters related to it,

d. Avoids use of excess quantity of solvents for purification, and

e. Process is suitable for plant scale manufacture.

The present invention is further illustrated by the following representative examples and does not limit the scope of the invention.

EXAMPLES

Details of HPLC method:

Column: Waters symmetry C-8, 4.6 X 100mm, 3.5 μηι

Detector: UV at 250 nm

Column temp.: 40 ^< C Buffer: 0.015 M monobasic potassium phosphate adjust pH with

diluted (0.2%) phosphoric acid

Mobile phase: A) acetonitrile and buffer (1 :4)

B) acetonitrile and buffer (4:1 )

Sample 1 mg/ml of olmesartan medoxomil in acetonitrile

preparation:

Injection 10 μΙ

volume:

Mode of elution: Gradiant

Flow: 1 .0 ml/min

Run time: 55.0 minutes

Olmesartan acid impurity (II) has an RRT of 0.16 with respect to olmesartan medoxomil (I).

Example 1 : preparation of olmesartan medoxomil (I) as per US 5616599:

To a mixture of acetic acid (76.8 ml) and water (25.6 ml) was added trityl olmesartan medoxomil (III) (10 g) and heated at 60°C for 1 .5 hours. Water (25.6 ml) was added and the reaction mixture was filtered to remove trityl alcohol. The filtrate was concentrated by rotary evaporator at 45-50 °C, to the residual mass was added toluene (20 ml) and the mixture was concentrated at 45-50°C. Olmesartan medoxomil (I) thus obtained had HPLC purity: Olmesartan medoxomil (I) (92.41 %); olmesartan acid impurity (II) (4.58%).

To the residue was added ethyl acetate (40 ml) and stirred at 25-30° for 1 -2 hours and 0- 5 ° for 1 -2 hours. The solid was filtered, washed with ethyl acetate and dried. Yield 5.1 g (73.9%); HPLC purity: Olmesartan medoxomil (I) (94.1 1 %); olmesartan acid impurity (I I) (4.31 %). Example 2: preparation of olmesartan medoxomil (I) as per the present invention:

To a mixture of acetic acid ( 37.5 ml) and water (12.5 ml) was added trityl olmesartan medoxomil (III) (10 g) and heated at 40-45 °C for 2 hours. Water (12.5 ml) was added and the reaction mixture was filtered to remove trityl alcohol. The filtrate was subjected to agitated thin film dryer, wherein the feed rate was of about 4 to 10 ml per minute, heating medium was jacketed hot water at 45-50 °C and vacuum was 70-75 mm/Hg. Crude olmesartan medoxomil (I) was recovered form ATFD. HPLC purity: olmesartan medoxomil (I) (97.81 %); olmesartan acid impurity (II) (0.97%).

To acetone (40 ml) crude olmesartan medoxomil (I) was added, the slurry was heated at 54-58 °C for 30 minutes and then stirred for 1 -2 hours at 0-5 °C, the solid was filtered. Wet solid was added to acetone (120 ml) and heated at 55-60°C. The solution was filtered. From the filtrate about 95 ml of acetone was distilled out at atmospheric pressure. The concentrated mass was stirred at 25-30 °C for 8-12 hours and then at 0-5 °C for 1 -3 hours. The solid was filtered, washed with acetone and dried. Yield 5.3 g (76.81 %). HPLC purity: olmesartan medoxomil (I) (99.67 %); olmesartan acid impurity (II) (0.07%).