FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
A PROCESS FOR THE PREPARATION OF OLMESARTAN MEDOXOMIL
UNICHEM LABORATORIES LIMITED, A COMPANY
REGISTERED UNDER THE INDIAN COMPANY ACT, 1956,
HAVING ITS REGISTERED OFFICE LOCATED AT
MAHALAXMI CHAMBERS, 2nd FLOOR,
22, BHULABHAI DESAI ROAD, MUMBAI-400 026.
MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed.

A PROCESS FOR THE PREPARATION OF OLMESARTAN MEDOXOMIL
TECHNICAL FIELD
The present invention relates to a process for the preparation of Olmesartan medoxomil. More particularly, the present invention relates to a simple, convenient and high yield process for making Olmesartan medoxomil.
BACKGROUND OF THE INVENTION
Olmesartan medoxomil is an angiotensin II receptor antagonist, used in the treatment of hypertension. The chemical name of Olmesartan medoxomil is 4-(l-Hydroxy-1-methyl ethyl)-2-propyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4-yl)methyl]-l-H-imidazole-5-carboxylic acid (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl ester and is represented by the following chemical formula (I).

(I)
US5616599 (Hiroaki Y, et al, 1997) patent discloses the Olmesartan medoxomil and its synthesis. According to the '599 patent the key intermediates used for the synthesis of Olmesartan medoxomil are (5-methyl-2-oxo-l, 3-dioxolen-4-yl) methyl -4- (1-hydroxy-

l-methylethyl)-2-propyl imidazole-5-carboxylate (II) and 4-[2-(trityl tetrazol-5-yl)-phenyl)] benzyl bromide (III).
.Br

^

NT
C(Ph)3
(III)

In the Example 61 of the '599 patent the condensation of both the intermediate is done in N,N- dimethylacetamide in the presence of potassium carbonate at 60°C. After the reaction, the mass is diluted with ethyl acetate and the ethyl acetate is washed with water. The distillation of the solvent under reduced pressure gives the residue and the resulting residue is column chromatographed to get the amorphous solid .The solid thus obtained is crystallized from diisopropyl ether to get the pure trityl olmesartan medoxomil as represented by formula (IV). The trityl olmesartan medoxomil is detritylated in aqueous acetic acid. After evaporation of aqueous acetic acid the residue is dissolved in toluene and again toluene is distilled to remove traces of water and acetic acid. The residue is again column chromatographed to get the Olmesartan medoxomil (I).

C(Ph),

(IV) Thus, in the described process to synthesize Olmesartan medoxomil column chromatography is involved and in the condensation step even after column chromatography crystallization is required to get the pure compound. The use of column chromatography is not feasible at commercial scale since it is very time consuming and the consumption of the solvents is very large to produce small amount of the compound. In the '599 patent synthesis of imidazole intermediate (II) is also described. One of the intermediate in the synthesis of imidazole intermediate (II) is ethyl-4- (1-hydroxy-1-methylethyl)-2-propyl imidazole-5-carboxylate (V). In Example 18 of the '599 patent

ethyl-4- (1 -hydroxy-1-methylethyl)-2-propyl imidazole-5-carboxylate (V) is condensed with 4-[2-( trityl tetrazol-5-yl)-phenyl)]benzyl bromide(III) to obtain ethyl-4- (1-hydroxy-l-methylethyl)-2-propyl-l-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate (VI).The said condensation reaction is done in N, N-dimethylformamide

C(Ph),
^^

by using sodium hydride as base. After the reaction is over the ethyl acetate is added to the reaction mass and washed several times with water. The ethyl acetate is distilled to get the residue. The residue thus obtained is purified by column chromatography to get the required compound (VI). The compound thus obtained is hydrolyzed by lithium hydroxide in dioxane and water (as described in Example 78). The lithium salt thus formed was extracted with ethyl acetate. The ethyl acetate is distilled to obtain the lithium salt. The lithium salt thus obtained is esterified with 4-chloromethyl-5-methyl-2-oxo-1, 3-dioxolene to get trityl olmesartan. The trityl olmesartan thus obtained is detritylated in aqueous acetic acid to get olmesartan medoxomil
The use of sodium hydride is very hazardous and difficult at commercial scale since it has fire hazard and if used as a suspension, the mineral oil remain trapped in the compound, which is difficult to separate out from the product. The product thus has to be purified by column chromatography, which is not feasible for commercial production and also not economical since lot of solvent is required.
The WO2004085428, on the basis of abstract also describes the synthesis of Olmesartan medoxomil. According to the process described the 4,4-dimethyl-2-propyl-l- {4-[2-(triphenylmethyl-tetrazole-5-yl) phenyl]phenyl}methyl-4,6-dihydrofuran[3,4-d]imidazol-6-one is ring-opened, the resulted 4-(l-hydroxy-l-methylethyl)-2-propyl-l-{4-[2-(triphenylmethyl-tetrazol-5-yl)phenyl]phenyl }methylimidazole-5-carboxylic acid is subsequently condensed with 4-bromo( or chloro)methyl-5-methyl-2-oxo-l,3-dioxacyclopentene under the action of alkali, after removing the triphenylmethyl

protective group, the purposed product, olmesartan medoxomil, is obtained. The use of said intermediate led to increase in number of stages.
WO2007017135 (2007, Zupancic S, et al) describe a process for the preparation of Olmesartan medoxomil wherein ethyl-4- (1-hydroxy-l-methylethyl)-2-propyl imidazole-5-carboxylate (V) was alkylated with 4-[2-(trityl tetrazol-5-yl)-phenyl)] benzyl bromide (III) in acetonitrile by using potassium carbonate base. Since in the alkylation 1.1 molar equivalent of 4-[2-( trityl tetrazol-5-yl)-phenyl)]benzyl bromide (III) is used it is difficult to get pure compound as per the process described.
WO2007047838 (2007, Sebastian S, et al) describes a process for preparing Olmesartan medoxomil. In the process disclosed instead of ethyl-4- (1-hydroxy-1-methyl ethyl)-2-propyl imidazole-5-carboxylate (V) a precursor of this namely dimethyl-2-propylimidazole-4, 5-dicarboxylate is N-alkylated with 4-[2-(trityl tetrazol-5-yl)-phenyl)] benzyl bromide (III) The alkylated compound thus obtained is manipulated at position C-4 and C-5 of imidazole ring through Grignard, hydrolysis, esterification and detritylation to get the olmesartan medoxomil. However Grignard reactions are not high yielding and if this was carried out on condensed product that is at the advanced stage the whole molecule is lost which is not economical method.
In view of the lack of process which is high yielding, easy to perform at industrial scale and provides pure intermediate there is still need for a alternative process which eliminates the shortcomings of the prior art methods.
OBJECT OF THE INVENTION
The object of the present invention is to provide a simpler process for the synthesis of Olmesartan medoxomil.
Another object of the present invention is to provide a Olmesartan medoxomil with a good yield and purity.

Another object of the present invention is to avoid the use of hazardous reagents during the synthesis of Olmesartan medoxomil.
Yet another object of the present invention is to provide an industrially scalable process for the preparation of Olmesartan medoxomil.
SUMMARY OF THE INVENTION
According to the present invention there is provided a process for the preparation of Olmesartan medoxomil of formula (I),

(I)
which comprises
a) N- Alkylation of ethyl-4- (1-hydroxy-l-methylethyl)-2-propyl imidazole-5-carboxylate
(V) with 4-[2-(trityl tetrazol-5-yl)-phenyl)] benzyl bromide (III) in presence of a base and
solvent.
b) Hydrolysis of the resultant ethyl-4- (1 -hydroxy-l-methylethyl)-2-propyl-l- {4-[2-
(trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate (VI) in presence of
base and solvent to obtain salt (VII)

c) Esterification of the resultant salt with 4-chloromethyl-5-methyl-2-oxo-l, 3-dioxolene in presence of base and solvent to obtain the trityl olmesartan (IV)
d) Detritylation of resultant trityl olmesartan in aqueous acid to get the olmesartan medoxomil (I).
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved, efficient and a simple process for making olmesartan medoxomil. According to the present invention the intermediates and final products are obtained in high yield and purity.
According to the present invention there is provided a process for the preparation of Olmesartan medoxomil (Scheme 1) comprising of
a) N- Alkylation of ethyl-4- (1 -hydroxy- l-methylethyl)-2-propyl imidazole-5-carboxylate
(V) with 4-[2-(trityl tetrazol-5-yl)-phenyl)] benzyl bromide (III) in presence of a base and
solvent.
b) Hydrolysis of the resultant ethyl-4- (1 -hydroxy- l-methylethyl)-2-propyl-l- (4-[2-
(trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate (VI) in presence of
base and solvent to obtain its salt (VII)
c) Esterification of the resultant salt with 4-chloromethyl-5-methyl-2-oxo-l, 3-dioxolene in presence of base and solvent to obtain trityl olmesartan (IV)
d) Detritylation of resultant trityl olmesartan in aqueous acid to get the olmesartan medoxomil (I).

CH,
CPh
;N-CPh,
CH,
CH
(.
0
3 ° H3C. OH
HNV y,H

3 K2C03/DMF
RT

V

VI

aq.KOH/Acetone


O
A.
OH
. N-CPh,
N 3
. N-CPh,
N 3
o o
IV

P H3C

CH,

O
A

CI
DMF/NaHC03 A

KO

O H3C H3C
N^N
CH,

75% aq.AcOH
VII

Scheme 1

In the synthesis of olmesartan medoxomil the step a) i.e. N-alkylation of ethyl-4- (1-hydroxy-l-methylethyl)-2-propyl imidazole-5-carboxylate (V) is done with 4-[2-(trityl tetrazol-5-yl)-phenyl)] benzyl bromide (III) by using dimethylformamide as a solvent and potassium carbonate as a base . In N- alkylation, alkylating reagent used is less than 1 molar equivalent preferably 0.95 to 0.80 molar equivalent, more preferably 0.90 molar equivalent with respect to imidazole (V) and in which the excess imidazole (V) is removed by salt formation. This reaction is carried out at 10 to 60°C, preferably at room temperature and more preferably at 25-30° C. The reaction is monitored by HPLC/TLC. After the completion of the reaction the water is added to the reaction mass, and stirred for further 30 minutes and the reaction mixture is filtered or extracted preferably filtered and washed with water. The precipitated product can also be extracted from a suitable water immiscible solvent like ethyl acetate. The wet cake suspended in dilute aqueous HC1 and stirred for 5-10 minutes. It is then filtered and washed with water. In the alkylation, the ethyl-4- (1-hydroxy-1-methylethyl)-2-propyl imidazole-5-carboxylate (V) is taken in excess so that the 4-[2-(trityl tetrazol-5-yl)-phenyl)] benzyl bromide (III) is totally consumed in the reaction. The excess imidazole derivatives (V) is removed by selective salt formation with acid in aqueous or oganic medium wherein the acid preferably used is aqueous hydrochloric acid. The acid used for salt formation can be inorganic or organic acid in water or any solvent can be used for salt formation. The imidazole derivative being secondary amine form the salt readily and dissolve in water while the alkylated product remain insoluble and obtained by filtration. The aqueous filtrate having imidazole (V) salt is basified and recovered by filtration or extraction. In the second step-b) the alkylated product is hydrolyzed with aqueous base in ketonic solvent. The base used is potassium hydroxide and the solvent used is water miscible ketone preferably acetone. The reaction is done at temperature 10 to 60°C preferably at room temperature, more preferably at 25-30°C. After completion of the reaction, the used solvent can be recovered by distillation. From the mixture non-acidic impurities is removed by extraction with a water immiscible solvent. The water immiscible organic solvent is added before or after the recovery of organic solvent used for the hydrolysis. The water immiscible organic solvent used for extraction of

impurities are cyclohexane, hexane and heptane preferably cyclohexane after the hydrolysis After the removal of the impurities the salt thus obtained is extracted with a water immiscible organic solvent. The ethyl acetate is preferably used for extraction and the required product is obtained as a thick residue by distillation of the solvent. To the residue acetonitrile is added, the resulting mixture is heated and slowly cooled to room temperature to obtain potassium salt as a crystalline powder. In the third step-c) the salt obtained is esterified with 4-chloromethyl-5-methyl-2-oxo-1, 3-dioxolene in presence of a base and a solvent. The reaction is carried out in presence of base like sodium bicarbonate, potassium carbonate preferably sodium bicarbonate and in a solvent like N, N-dimethylformamide, N, N-dimethylaceatamide preferably N,N-dimethylformamide. The reaction is done at 10-80°C preferably at 35-60°C more preferably at 45-50°c. After the completion of reaction the reaction mass was cooled to room temperature and water is added to the reaction mass and extracted with ethylacetate. The distillation of the solvent gives trityl olmesartan. In the 4th step-d), the detritylation of the trityl olmesartan is done in aqueous acetic acid. The reaction is done at 10-80°C preferably at 20 to 40°C more preferably at 25-30°C. After completion of the reaction olmesartan is extracted in ethyl acetate. The ethyl acetate layer is washed with water and dried over sodium sulphate. The distillation of the solvent gives the olmesartan. The olmesartan medoxomil thus obtained can be crystallized with ethanol if required.
Although the invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the invention, will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the spirit or scope of the present invention as defined.

EXAMPLES
The following examples are presented for illustration only, and are not intended to limit
the scope of the invention or appended claims.
Examplel:
Ethyl-4- (1 -hydroxy- l-methylethyl)-2-propyl-l- {4-[2-(trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate (VI)
107.5 gm (0.19 mole) of 4-[2-(trityl tetrazol-5-yl)-phenyl)] benzyl bromide (III) and 250.0 ml N, N-dimehylformamide was charged in clean and dry round bottom flask with a overhead stirrer. To the resulting mass 50.0 gm (0.20 mole) of ethyl-4- (1-hydroxy-1-methylethyl)-2-propyl imidazole-5-carboxylate (V) was added and stirred for 5-10 mins. Potassium carbonate 115.0 gm (0.83 mole) was added in the resulting suspension and stir at 25-30°C for approx 48.0 hrs and progress of the reaction was monitored by TLC. After the reaction was over 750 ml water was added to the reaction mass, stirred for 30 mins and filtered. The solid cake was washed with 250.0 ml water. The solid thus obtained was charged again in 500.0 ml 1.0% aqueous HC1 in a round bottom flask and stirred for 10.0 mins, filtered and washed with 250.0 ml water. It was unloaded and dry in air oven at 90°C to obtain 124.0 gm of the title compound. (Yield 89.76%)
Example 2:
Potassium-4- (1 -hydroxy-1 -methylethyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methyIimidazole-5-carboxylate (VII)
100.0 gm (0.139 mole) of the compound obtained in examplel and 2.5 L acetone was charged at room temperature in a clean round bottom flask with overhead stirrer. The suspension thus obtained was stirred to get clear solution. To this aqueous solution of potassium hydroxide prepared by dissolving 31.3 gm potassium hydroxide in 600.0 ml water was added. The resulting mixture was stirred at 25-30°C for approx 6.0 hr to complete the reaction. The progress of the reaction was monitored on TLC. After the completion of the reaction 1.50 L of cyclohexane was added and stirred. The upper layer

was separated. The lower aqueous layer was distilled out to remove acetone and 1.0 L of ethyl acetate was added to extract the potassium salt. The ethyl acetate layer was washed with 500.0 ml water and dried over sodium sulphate. Distillation of the solvent under reduced pressure gave 98.0 gm of the required compound. (Yield 96.2%)
Example 3: Trityl Olmesartan
80.0 gm (0.11 mole) of compound obtained in example 2 and 400.0 ml N, N -Dimethyl formamide was charged at room temperature in a clean and dry round bottom flask equipped with overhead stirrer. The resulting mixture was cooled to 10°C and 4.62 gm of sodium bicarbonate was added to it. The resultant mixture was stirred for 10-15 mins at this temperature and a solution of 18.3 ml (0.11 mole) 4-chloromethyl-5-methyl-2-oxo-l, 3-dioxolene in 18.3 ml N, N-Dimethylformamide was added drop-wise by maintaining the temperature at 10-15°C. The temperature of the mixture was raised to 50°C and maintain for 3.0 hrs for completion of the reaction. The progress of the reaction was monitored with TLC (hexane: ethyl acetate 1:1). After the reaction was over it was cooled to room temperature and 450.0 ml of water was added, stirred and 450.0 ml of ethyl acetate was added. The ethyl acetate layer was separated and washed with brine solution. It was dried over sodium sulphate and distilled under reduced pressure to obtain 75.0 gm of trityl olmesartan. (Yield 85.0%)
Example 4: Olmesartan
25.0 gm (0.031 mole) of the trityl olmesartan obtained in example 3 and 250.0 ml of 75.0 % aqueous acetic acid was charged in a clean round bottom flask equipped with overhead stirrer. The resulting reaction mass was stirred at 25-30°C till the completion of the reaction. The progress of the reaction was monitored on TLC (ethyl acetate). After the completion of the reaction 70.0 ml water was added, stirred and cool to 10°C, the trityl alcohol thus precipitated was filtered. The filtrate was extracted with 800.0 ml ethyl acetate, washed with water and dried over sodium sulphate. The distillation of the ethyl acetate gave 15.0 gm of olmesartan. (Yield 86.2%)

We Claim:
1. A process for the preparation of Olmesartan medoxomil of formula I

(I)
Which comprises
a) N- Alkylation of ethyl-4- (1 -hydroxy-l-methylethyl)-2-propyl imidazole-5-carboxylate (V) with 4-[2-(trityl tetrazol-5-yl)-phenyl)] benzyl bromide (III) in presence of a base and solvent.
b) Hydrolysis of the resultant ethyl-4- (1-hydroxy-l-methylethyl)-2-propyl-l- {4-[2-(trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate (VI) in presence of base and solvent to obtain its salt (VII).
c) Esterification of the resultant salt with 4-chloromethyl-5-methyl-2-oxo-l, 3-dioxolene in presence of base and solvent to obtain trityl olmesartan (IV).
d) Detritylation of resultant trityl olmesartan in aqueous acid to get the olmesartan medoxomil (I).
2. A process of claim 1-a), wherein the solvent used for alkylation is N, N-dimethylformamide, in presence of potassium carbonate as a base and at a temperature between 10-60°c, preferably at room temperature and more preferably at 25-30°c.

3. The process of claim 1-a), wherein the alkylating reagent, 4-[2-(trityl tetrazol-5-
yl)-phenyl)] benzyl bromide (III) used is less than 1 molar equivalent preferably
0.95 to 0.80 molar equivalent, more preferably 0.90 molar equivalent with
respect to imidazole (V).
4. The process of claim 1-a), wherein the excess imidazole (V) from isolated product is removed by salt formation with acid in aqueous or organic medium.
5. The process of claim 4, wherein the acid preferably used is aqueous hydrochloric acid.
6. A process of claiml-b), wherein the base used for hydrolysis is aqueous potassium hydroxide and solvent is acetone.
7. A process of claim 1-b), wherein the hydrolysis done at 10-60°c, preferably at room temperature and more preferably at 25-30°C
8. The process of claim 1-b), wherein the reaction mass is extracted with cyclohexane, hexane and heptane preferably cyclohexane after the hydrolysis.
9. A process of claim 1-c), wherein the base used for esterification is sodium bicarbonate or potassium carbonate preferably sodium bicarbonate in a solvent N, N-dimethylformamide or N,N-dimethylacetamide preferably N, N-dimethylformamide at a temperature range of 10-80°C, preferably at 35-60°C and more preferably at 45-50°C.
10. The process of claim 1-d) wherein the detritylation is done by using aqueous acetic acid at a temperature range of 10-80°C, preferably at 20 to 40°C more preferably at 25-30°C.
11. A process for the preparation of compounds of formula (I) substantially as herein described and illustrated with reference to the accompanying examples.

ABSTRACT:
The present invention relates to an improved high yields and high throughput process for the preparation of 4-(l-Hydroxy-1-methyl ethyl)-2-propyl-l-[[2'-(lH-tetrazol-5-yl)[l,l'-biphenyl]-4-yl)methyl]-l-H-imidazole-5-carboxylic acid (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl ester, known as Olmesartan medoxomil which comprises of N-alkylation of ethyl-4- (1-hydroxy-1-methylethyl)-2-propyl imidazole-5-carboxylate (V) with 4-[2-(trityl tetrazol-5-yl)-phenyl)] benzyl bromide (III), its hydrolysis with aqueous base, esterification with 4-chloromethyl-5-methyl-2-oxo-l, 3-dioxolene and detritylation with aqueous acid.