FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
THE PROVISIONAL SPECIFICATION
(See section 10)
1. AN IMPROVED PROCESS FOR THE PREPARATION OF OLMESARTAN MEDOXOMIL.
2. CADILA PHARMACEUTICALS LTD., "CADILA CORPORATE CAMPUS", SARKHEJ-DHOLKA ROAD, BHAT, AHMEDABAD, 382210, GUJARAT, INDIA, AN INDIAN COMPANY.
3. THE FOLLOWING SPECIFICATION DESCRIBES AND ASCERTAINS THE NATURE OF THIS INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

TITLE : An improved process for the preparation of Olmesartan Medoxomil,

FIELD OF THE INVENTION:
The present invention relates to an improved process for the preparation of Olmesartan medoxomil. Olmesartan Medoxomil is a non-peptide new angiotensin-II receptor antagonist used for the treatment of hypertension.

BACKGROUND OF THE INVENTION
Olmesartan medoxomil is known by two names,
(a) (5-MethyI-2-oxo-1,3-dioxolen-4-yl)methyl 4-( 1 - hydroxy-1 -methylethyl)-2-propyl-1 ~[4-[2(tetrazole-
5 yl)phenyl]phenyl]methyl imidazole- 5 -carboxylate
(b) 4-(l-Hydroxy-l-methylethyl)-2-propyl-l-[[2'-(lH-tetrazol-5-yl)[l,1-biphenyl]-4-yl]methyl]-lH-
imidazol-5-carboxylic acid (5-methyl-2-oxo-l,-3 dioxol-4-yl)methyl ester, and has a CAS No. [ 144689-
63-4].
The structural formula is represented below:

OLMESARTAN MEDOXOMIL
The prior art synthetic methods involve coupling reaction between the substituted imidazole and substituted biphenyl methyl bromide.
J. Med. Chem. 1996 vol. 39 No.1, page 323-38 describes the synthesis of Olmesartan medoxomil and the process intermediates is illustrated as follow in Scheme-1:

Et02C H Et02C^N

CH3MgCI,THF.MDC B1°^A f~ DMA/K0Bu'
TTBB
-Oto-10°C
HO



N-CPh3
,N-CPhq
LiOH.H20
1,4-dioxane/5-10DC


HO/ N,
.C=0
Q
CPh,
Y%'
CK^-O
K2C03 at 60°C

Q
o

25% Acetic acid
60DC

HO, N^
o
Y°

US 5616599 describes a process for the preparation of olmesartan medoxomil as follows. 4-(l-hydroxyl-l-methylethyl)-2-propyl imidazole-5carboxylic acid is reacted with 5-methyl-2-oxo-l, 3-dibxolene-4-yl)methyl chloride using N,N-diisopropyl ethyl amine as base in N,N-dimethyl acetamide at 60°C to give (5-methyl-2-oxo-lJ3^dioxolen-4-yl)methyl4-(l-hydroxy-l-methylethyl)-2-propyl imidazole-5-carboxylate. The resulting product is coupled with N-(triphenylmethyI)-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole [herein referred to as TTBB] at 60°C in N, N-dimethyl acetamide using potassium carbonate as base to give protected olmesartan medoxomil. The protected olmesartan medoxomil is deprotected using 75 % acetic acid to give olmesartan medoxomil.
This process involves column chromatographic purification of intermediates which is not desirable on commercial scale operation.
US 5616599 describes another process for the preparation of olmesartan Medoxomil which involves Grignard addition of methyl Magnesium chloride on diethyl 2-propyl imidazole-4, 5-dicarboxylate in tetrahydrofuran at -30 to -20°C to give ethyl-4-(l-hydroxy-l-methylethyl)-2-propylimidazoIe -5-carboxylate , which is coupled with TTBB using sodium hydride as base in N, N-dimethylformamide at 60°C to give ethyl-4-(l-hydroxy-1-methylethyl) 2-propyl- l-[[2*-[2-(triphenylmethyI)-2H-tetrazoI-5y!]biphenyl-4-yl]methyl]imidazole -5-carboxylate. The product thus formed is hydrolyzed using lithium hydroxide monohydrate as base in 1,4-dioxane at 5-10°C to give lithium salt of 4-(l -hydroxy-1-methylethyl) 2-propyl- l-[[2'-[2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole -5-carboxylic acid , which is then coupled with 5-methyl-2-oxo-l,3-dioxolene-4-yl) methyl chloride using K2CO3 as base in N,N-dimethylacetamide at 50°C to give trityl protected olmesartan medoxomil which on deprotection using 75% acetic acid gives Olmesartan Medoxomil.
During the condensation of ethyl-4-(l-hydroxy-l-methylethyl)-2-propylimidazole -5-carboxylate , with TTBB using sodium hydride as base in N, N-dimethylformamide, various impurities are formed, and isolation of the product involves extractive workup
It is therefore a long-felt need to provide an improved process to the industry which can be performed on a commercial scale, which does not involve chromatographic purification, does not use carcinogenic , solvent and which does not involve multi-step extractive workup and gives olmesartan medoxomil in high purity [> 99.2% by HPLC]

SUMMARY OF THE INVENTION:
The main object of the present invention is to provide a process for the commercial production of
Olmesartan medoxomil.
Another object of the present invention is to provide a process without the use of chromatographic
purification in the steps [1] and [2] of the present invention.
Yet another object of the present invention is to provide a process without the use of carcinogenic solvent.
Yet another object of the invention is to provide a process which involve coupling reaction between the
substituted imidazole and substituted biphenyl methyl bromide using an organic solvent, preferably
ketonic solvent such as acetone, using a base such as carbonates and bicarbonates, preferably carbonates
such as anhydrous potassium carbonate and phase transfer catalyst in non-aqueous system.
Yet another object of the present invention is to provide a process with reduced levels of impurities in
each stage and give olmesartan medoxomil of HPLC purity >99.5 %

DETAILED DESCRIPTION:
In accordance with the present invention, the synthesis of olmesartan medoxomil comprises:
[1] Reacting diethyl-2-propyl imidazole-4,5-dicarboxylate with methyl magnesium halide in an organic
solvent to give after workup, ethyl-4-(l-hydroxy-l-methylethyl)-2-propylimidazole -5-carboxylate,
[2] Reacting ethyl-4-(l -hydroxy-1 -methyl ethyl )-2-propylimidazole -5-carboxylate with N-
(Triphenylmethyl)-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole using an organic solvent, preferably
ketonic solvent such as acetone, and using a base such as carbonates and bicarbonates, preferably
carbonates such as anhydrous potassium carbonate and phase transfer catalyst in non-aqueous system
to give after workup, ethyl-4-(l-hydroxy- 1-methylethyl) 2-propyl- l-[[2'-[2-(triphenylmethyl)-2H-
tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate,
[3] Reacting ethyI-4-( 1 -hydroxy-1 -methylethyl) 2-propyl- 1 -[[2 '-[2-(triphenylmethyl)-2H-tetrazoI-
5ylJbiphenyl-4-yl]methyl]imidazole -5-carboxylate in an organic solvent with LiOH.H20 to give
Lithium salt of 4-( 1 -hydroxy-1 -methylethyl) 2-propyl- 1 -[[2 '-[2~(triphenylmethyl)-2H-tetrazol-
5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylic acid , after work-up,
[4] Reacting Lithium salt of 4-(l-hydroxy-1-methylethyl) 2-propyl- l-[[2'-[2-(triphenylmethyl)-2H-
tetrazol-5yl] biphenyl-4-yl] methyl] imidazole -5-carboxylic acid in an organic solvent with 4-
Chloromethyl 5-methyl 1,3- dioxolene 2-one; optionally using iodide exchange catalysis and using a base
to give after workup, trityl protected olmesartan medoxomil,
[5] Reacting trityl protected olmesartan medoxomil with aqueous acetic acid to give olmesartan.
medoxomil, which is further, purified to give pharmaceutically acceptable grade of olmesartan
medoxomil.
For step-[1]:
Methyl magnesium halide used for the reaction is methyl magnesium chloride or methyl magnesium
bromide or methyl magnesium iodide.
Solvent used for this step is selected from ethers such as THF, 2-Methyl THF, 1,2-dimethoxy ethane,
dibutyl ether, aromatic hydrocarbon solvents such as benzene, toluene, xylene optionally mixtures
thereof; the more preferred solvent is THF.
The temperature for the reaction is from about -20 to 45°C preferably from -15 to 25 C

After the reaction is over the reaction mass is worked up using ammonium chloride solution and compound is isolated by extractive workup.
For step-[2]:
The base used for the coupling is selected from carbonates and bicarbonates such as anhydrous Na2CO3, K2C03, CS2CO3, NaHC03, KHCO3, BaC03,CaCO3 or mixtures thereof; more preferably anhydrous potassium carbonate,
The solvent for the reaction is selected from ketonic solvents such as acetone, methyl ethyl ketone, methyl Isobutyl ketone, 2-pentanone, 3-pentanone, cyclopentanone,cyclohexanone ,; optionally mixtures thereof The preferred solvent is acetone, methyl ethyl ketone, methyl isobutyl ketone , more preferably acetone. Nitriles such as acetonitrile, propionitrile;
Alcohols such as ethanol, propanol, isopropyl alcohol, tert. butanol,, n-butanol and their like, optionally mixtures thereof;
. Aromatic hydrocarbon solvents such as benzene, toluene, xylene or mixtures thereof preferably toluene. Aliphatic and alicyclic solvents such as hexane, heptane, cyclohexane, methyl cyclohexane or mixtures thereof;
Substituted amide group of solvents such as N,N- dimethyl formamide, N,N-dimethyl acetamide, N-methyl pyrrolidone, 1,3- dimethyl 2-imidazolidinone, tetramethyl urea,and their like , optionally mixtures thereof;
The temperature for the reaction is selected from 0 to 1'50°C, and is normally depending on the type of solvent and the rate of reaction desired, therefore the preferred temperature depends on the type of solvent used, preferably from 10 to 100°C,
Phase transfer catalyst used for the reaction is selected from Quaternary ammonium salts such as :
N(R1R2R3R4)X where R1,R2,R3, and R4 is G to C13 alkyl or aralkyl group, cycloalkyl, aryl, or heterocyclyl. X is a monovalent anion .The preferred catalyst is
Triethyl benzyl ammonium chloride, or Tetrabutyl ammoniun bromide, or tetrabutyl ammonium hydrogen sulfate, preferably Tetrabutyl ammoniun bromide; Quat. Phosphonium salts and PEG ethers. For step- [3]:
The solvent used for the reaction is selected from ether group of solvents such as THF, 2- methyl THF, methyl tert. butyl ether, monoglyme and their like ; optionally mixtures thereof, preferably THF.

The temperature of the reaction is from -10 to +50°C preferably below 10°C for addition of base and
about 20 to 30 C after the addition of base. The material obtained after extractive work up is isolated as
such and is carried forward for the next step.
For step-[4]:
The solvent used for the reaction is selected from N,N-dialkyl amide group of solvents such as
DMF,DMA,NMP and sulfoxides such as DMSO, ketonic solvents such as acetone, MEK, MIBK;
optionally mixtures thereof.
The base used for the' condensation is selected from tertiary amines such as triethyl amine, diethyl aniline
N-methyl morpholine, diisopropyl ethyl amine; preferred base is triethyl amine.
Carbonates and bicarbonates of alkali metals and alkaline earth metal compounds such as Na2CO3 ,
K2C03,CaC03BaC03, NaHC03) KHCO3.
Metal iodides can be used to exchange with chlorine of 4- Chloromethyl 5-methyl 1,3- dioxolene 2-one to
accelerate the rate / yield of reaction.
The temperature of the reaction is from ~20°C to 100°C preferably below 10°C during addition and 25 to
100°C for completing the reaction after the addition is over. The compound is isolated by suitable
extractive procedures.
For step-[5]:
For deprotecting trityl olmesartan medoxomil, the requirement is the reaction of this compound with an
acid preferably an aqueous acid.
The acid used for trityl deprotection is selected from aq. H2SO4, aqueous hydrochloric acid, aqueous
phosphoric acid, aqueous acetic acid, aqueous formic acid and their like, preferably aqueous acetic acid.
The temperature range selected for the deprotection is from 0 to 100°C, preferably between 35 to 80°C.
The compound is then crystallized from 2- propanol, which is further purified using methyl ethyl ketone.
For all synthesis steps mentioned above the progress of the reaction is monitored using a thin layer
chromatography.
The present invention is illustrated with following examples, which does not limit the scope of the
invention.
Step[l]
Preparation of Ethyl-4-( 1 -hydroxy-1 -methyl ethyl)-2-propylimidazole -5-carboxylate
To a 3M solution of MeMgCl(55.86 g, 0.74 mol) in tetrahydrofuran was added a solution of diethyl 2-
propyl imidazole- 4,5-dicarboxylate (50 g,0.19 mol) in tetrahydrofuran (200 ml) at -10 to 0°C under N2

atmosphere. The mixture was stirred at -5 to 0°C for 10 minutes. Reaction mass was quenched into 400 ml 25 % ammonium chloride solution followed by extraction with ethyl acetate (300 ml). The organic phase was separated, washed with brine, dried over Na2S04, and concentrated in vacuo to give a syrup, which was crystallized using diisopropyl ether. Yield: 85-90 %, Purity by HPLC: 88-93 %.
Step- [2]
Preparation of Ethyl-4-'(l-hydroxy-l-methylethyl) 2-propyl- l-[[2'-[2-(triphenylmethyl)-2H-tetrazol-
5yl]biphenyl-4-yl]methyI]imidazole-5-carboxylate
Mixture of stage- 1 compound (41 g, 0A1 mol), potassium carbonate (47g, 0.34 mol) and tetrabutylammonium bromide (4.9 g, 0.01 mol) in acetone was stirred at room temperature for lhr. Then TTBB (93% Purity, 92.89g, 0.15 mol) was charged, refluxed for 14hrs. Potassium salts were filtered off from the reaction, mass and the filtrate was charcoalised for lhr. It was filtered over celite bed and the filtrate was distilled off completely to get a semi solid. 250 ml of Methanol was added to the residue and stirred for 2-3 hrs. Formed solid product was filtered and washed with chilled methanol. Yield: 80-85%, Purity by HPLC: 85-90%.
Step- [3]
Preparation of lithium salt of 4-(l-hydroxy-1-methylethyl) 2-propyl- l-[[2'-[2-(triphenylmethyl)-2H-
tetrazol-5yl] biphenyl-4-yl] methyl] imidazole -5-carboxylic acid
To a solution, of stage- 2 (105 g, 0.14 mol) material in tetrahydrofuran was added LiOH.H2O (7.8 g, 0.18
mol) solution below 10°C. The reaction mixture was stirred at room temperature for 15 hours. Reaction
mass was concentrated under vacuum at 35°C to 1/4th of its volume. 300 ml of ethyl acetate and NaCl
(130 g) were added to the residue under stirring. The organic phase was separated, dried over sodium
sulphate and concentrated under vacuum to get the product. The crude product was taken as such to the
next stage.
Step- [4]
Preparation of trityl protected olmesartan medoxomil
To the solution of stage-3 (97 g, 0.13 mol) material in N, N-dimethyl acetamide(200 ml) was added
triethylamine(12.7 g, 0.12 mol), stirred at room temperature for 0.5hours. 4-Chloromethyl-5-methyl-l, 3-
dioxolene 2-one (85% purity, 37.3 g, 0.25 mol) was added below 10°C. The mixture was stirred at 50-

55°C for 4 hours, checked TLC. Dichloromethane (40.0 ml) and chilled water (500 ml) were added under stirring. The organic phase was separated, given brine wash (50 ml), dried over sodium sulphate and concentrated under vacuum to get a residue. To the residue methanol was added, stirred for 1hr, cooled to 5-10°, filtered and washed with chilled methanol. Yield: 75-80%, Purity by HPLC: 96-98%.
Step- [5] -
Preparation of olmesartan medoxomil
To the suspension of stage-4 (50g, 0.06 mol) material in 250 ml 75% acetic acid was stirred at 50-55°C
for 1.5hrs and cooled to 5-10°C. The by-product trityl alcohol was filtered off and washed with 75%
acetic acid. The filtrate was concentrated under vacuum to get syrup, which was crystallized using
isopropyl alcohol. Yield: 85-88%, Purity by HPLC: 95-98%.
The material was further purified with ethyl methyl ketone. It was filtered and washed with ethyl methyl
ketone and dried to give olmesartan medoxomil of pharmaceutically acceptable quality.
Yield: 70-75%, Purity by HPLC: 99.3-99.7%.