DESC:FORM 2
THE PATENT ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
(See section 10; rule 13)

“AN INDUSTRIALY SCALABLE PROCESS FOR THE PREPARATION OF OLMESARTAN MEDOXOMIL”

HIKAL LIMITED, an Indian Company, of 3A & 3B, International Biotech Park, Hinjewadi, Pune – 411057, Maharashtra, India

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of Olmesartan Medoxomil of formula (I) in single solvent in robust and industrially scalable manner.

BACKGROUND OF THE INVENTION

Olmesartan Medoxomil, is described chemically as 2,3-dihydroxy-2-butenyl 4-(1 hydroxy-1-methylethyl)-2-propyl-1-[p-(o-1H-tetrazol-5-ylphenyl) benzyl]imidazole-5 carboxylate, cyclic 2,3- carbonate. Olmesartan Medoxomil is found to be an excellent Angiotensin II receptor antagonist activity and useful as antihypertensive drug for the therapy and prophylaxis of heart diseases.

Several publications such as US 5,616,599; US 5,744,612; US 2005/0119488; US 2006/0074117 were disclosed the preparation of Olmesartan Medoxomil. The known processes, however, have one or the other disadvantages, for example :(i) use of expensive, explosive reagent such as sodium azide; (ii) use of multiple and high boiling solvents such as toluene, xylene; (iii) tedious process for removal of impurities; (iv) long cycle time (20-24 hrs.);(v) tedious and troublesome operations, extractions; multiple distillations for removal of multiple solvents; (vi) low chemical yield and purity; (vi) non-economic process. Thus, these processes are not an industrially advantageous.

To overcome the limitations of the processes known in the art, the inventors of the present invention have developed a robust, industrially scalable process for preparation of Olmesartan Medoxomil with high yield and greater chemical purity.

SUMMARY OF THE INVENTION

An aspect of the present invention provides an efficient process for the preparation of Olmesartan Medoxomil of formula (I), which comprises the steps of:

a) obtaining a compound of formula (IV) by reacting a compound of formula (II) with compound of formula (III) in presence of an inorganic base, in single solvent, with or without using a catalyst;

b) obtaining a compound of formula (VIII) by sequential reaction conversions of compound formula (IV) without isolation of compound of formula (V); where the sequential reaction conversions comprising of:
i. obtaining a compound of formula (V) by reacting compound of formula (IV) in presence of inorganic base, water in single solvent;

ii. condensing compound of formula (V) with compound of formula (VII) in presence of inorganic base in single solvent, with or without using a catalyst to obtain a compound of formula (VIII);

c) deprotecting compound of formula (VIII) using an acid in single solvent to obtain a compound of formula (I).

DETAILED DESCRIPTION OF THE INVENTION

The present invention now will be described more fully hereinafter. The invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification, and in the appended claims, the singular forms “a”, “an”, “the”, include plural referents unless the context clearly indicates otherwise.

The present invention provides an efficient process for the preparation of Olmesartan Medoxomil of formula (I) via. substantially pure intermediate of formula (IV), (VIII) and the said process is illustrated in the following scheme.

The term “substantially pure” as used herein, refers to the purity of compound greater than 96%; preferably greater than 99%.

In accordance with the objectives, the present invention provides a cost-efficient process for the preparation of Olmesartan Medoxomil of formula (I) and intermediates thereof using single reaction solvent.

In one embodiment, the instant invention provides the preparation of Olmesartan Medoxomil of formula (I)consisting of three steps [step (a), step (b) and step (c)] which involve isolating solid material; thus, the process industrially feasible.

In another embodiment, the instant invention provides the preparation of Olmesartan Medoxomil of formula (I),wherein compound of formula (IV) is obtained with high chemical purity and without formation of impurities of formula (IV-a).

In another embodiment, the instant invention provides the preparation of Olmesartan Medoxomil of formula (I),wherein compound of formula (VIII) is obtained without isolation of intermediates (V), avoiding the formation compound of formula (VI) and impurity of formula (VIII-a); thus, the process is economically viable.

In another embodiment of present invention, an inventor of present invention develops a process for preparation potassium salt of formula (V) and avoid the formation of trityl Olmesartan dihydrate formula (VI)which is confirm by the moisture content (NMT 1.0%).

In another embodiment of present invention, wherein the inventor of present invention develops a process, wherein byproduct triphenylcarbinol is removed by using single reaction solvent such as methanol and by simple filtration technique without use of secondary solvent and other tedious purification techniques.

In another embodiment, the instant invention provides the preparation of Olmesartan Medoxomil of formula (I), with high chemical purity and without formation of impurities of formula (I-a) and (I-b), thus the overall process is industrially scalable.

In another embodiment of the present invention, wherein the inorganic base is selected from group consisting of sodium methoxide, sodium ethoxide, sodium carbonate, potassium hydroxide, potassium carbonate, potassium tert-butoxide, potassium methoxide, potassium ethoxide and the like.

In another embodiment of the present invention, wherein the catalyst is selected from tetra butyl ammonium bromide, tetra propyl ammonium bromide, tri butyl benzyl ammonium bromide, tetra octyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulphate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide, ethyl triphenyl phosphonium bromide more preferably tetra butyl ammonium bromide or alkyl iodides like sodium iodide, potassium iodide and lithium iodide.

In another embodiment of the present invention, wherein solvent is selected from water, ketonic solvent, alcoholic solvent, and chlorinated solvent.

In another embodiment of the present invention, wherein a ketonic solvent is selected formacetone, methyl ethyl ketone, methyl isobutyl ketone, methyl amyl ketone, cyclohexanone, di isobutyl ketone, acetophenone, butanone, ethyl isopropyl ketone and the like; preferably acetone.

In another embodiment of the present invention, wherein an alcoholic solvent is selected from methanol, ethanol, isopropanol, n-butanol, glycerol, tert-butyl alcohol, 2-pentanol, propylene glycol and the like; preferably methanol.

In another embodiment of the present invention, wherein chlorinated solvent is selected from dichloromethane, dichloroethane, carbon tetrachloride, perchloromethane, vinyl chloride and the like preferably dichloromethane.

In another embodiment of the present invention, wherein acid is selected from acetic acid, sulfuric acid, hydrochloric acid, and the like.

In another embodiment of the present invention, wherein a preparation of compound of formula (IV) and formula (VIII) is performed in ketonic solvent.

In another embodiment of the present invention, wherein a preparation of compound of formula (I) is performed in alcoholic solvent and purification is performed in ketonic solvent.

In another embodiment of the present invention, wherein the reaction temperature for preparation of compound of formula (IV) is 25°C to 60°C and reaction time is 6-8 hrs.

In another embodiment of the present invention, wherein the reaction temperature for preparation of compound of formula (VIII) is 25°C to 50°C and reaction time is 4-5 hrs.

In another embodiment of the present invention, wherein the deprotection reaction is performed in presence of catalytic acid.

In another embodiment of the present invention, wherein the said acid used is selected from formic acid, acetic acid, benzoic acid, oxalic acid, sulfuric acid, sulfurous acid, p-toluene sulfonic acid, nitric acid, nitrous acid, phosphoric acid, and carbonic acid, and binary acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, and hydrocyanic acid, most preferably hydrochloric acid.

In another embodiment of the present invention, wherein the reaction temperature for preparation of compound of formula (I) is 5°C to 20°C and reaction time is 2-3 hrs.

The present invention will now be further explained in the following examples. However, the present invention should not be construed as limited thereby.

EXAMAPLES

Example 1:Preparation of compound of formula (IV).
To a solution of compound of formula (II, 150 Kg) in acetone (900 L), compound of formula (III,375.82 Kg), potassium carbonate (189.75 Kg) & tetra butyl ammonium bromide (12.06 Kg) was added at RT. The reaction mixture was heated at 55°C to 60°C for 6 to 8 hrs. The progress of the reaction was monitor by HPLC. The reaction was quenched by adding water at 55°C to 60°C and further heated for 2 hrs. Reaction mass was cooled to 45°C to 50°C, filtered and wet solid was washed with water. The wet solid again treated with a mixture of acetone and water at 25°C to 35°C for 2-3 hrs. The reaction mass was filtered, dried under vacuum at to obtain compound (IV, 441Kg, 98.53% yield, 96% HPLC purity, Moisture content NMT 1.0%).

Example 2: Preparation of compound of formula (VIII).
To the solution of acetone (2150 L) and water (43 L), potassium hydroxide (77.39 Kg) was added at RT and heated to 40°C to 50°C till clear solution. To above clear solution a compound of formula (IV, 430 Kg) was charged and stirred at 40°C to 50°C for 4-5 hrs. The completion of reaction was monitored by HPLC.The organic layer was separated and potassium iodide (12.9 Kg), sodium bicarbonate (50.35 Kg)was added at 40°C to 50°C in 15-30 min. The compound of formula (VII)(115.82 Kg) was charged to reaction mixture and stirred at 40°C to 50°C for 4-6 hrs. The completion of reaction was monitor by HPLC. After completion, the reaction mixture was filtered and washed with acetone. The solvent was removed under vacuum to minimum stirrable volume and reaction mass was cooled to -5°C to -10°C for 1-2 hrs. The reaction mass was filtered, washed with chilled acetone, dried to obtain compound (VIII, 427.5 Kg, 89% yield,99.4% HPLC purity, LODNMT 1.0%).

Example 3: Preparation of compound of formula (I).
To a cold solution of methanol (280 L) and conc. hydrochloride acid (21 L), a compound of formula (VIII, 180 Kg) was charged at 10°C to 15°C. The reaction mixture was stirred at 10°C to 15°C for 2-3 hrs. The completion of reaction was monitor by HPLC. After completion, the reaction mixture was filtered to remove the byproduct tritylmethyl ether. To the wet solid, methanol (280 L) was charged and stirred 20°C to 30°C for 10-20 min. The reaction mass was filtered and to the combined filtrate dichloromethane (980 L) was charged and cooled the solution to10°C to 20°C. The pH of reaction solution was maintained at 5 to 6 using aq. sodium bicarbonate solution. The aq. layer separated and extracted with dichloromethane. The combined organic layer washed with saturated sodium chloride solution and organic layer separated. The organic layer treated with activated carbon, filtered and solvent was removed under vacuum. To the concentrated reaction mass, acetone (1540 L) was charged and heated at 50°C to 60°C till dissolution observed. The solvent was removed to minimum stirrable volume, and the reaction solution was cooled to 0°C to 5°C for 1-2 hrs. The reaction mass was filtered, washed with chilled acetone, dried to obtain compound (I, 84 Kg, 86.08% yield, 99.9% HPLC purity, LOD NMT 0.5%).
,CLAIMS:We claim:

1) A process for the preparation of Olmesartan Medoxomil of formula (I), which comprises the steps of:

a) obtaining a compound of formula (IV) by reacting a compound of formula (II) with compound of formula (III) in presence of an inorganic base, in single solvent, with or without using a catalyst;

b) obtaining a compound of formula (VIII) by sequential reaction conversions of compound formula (IV) without isolation of compound of formula (V); where the sequential reaction conversions comprising steps of:
i. obtaining a compound of formula (V) by reacting compound of formula (IV) in presence of inorganic base, water in single solvent;

ii. condensing compound of formula (V) with compound of formula (VII) in presence of inorganic base in single solvent, with or without using a catalyst to obtain a compound of formula (VIII);

c) deprotecting compound of formula (VIII) using an acid in single solvent to obtain a compound of formula (I).

2) The process as claimed in claim 1, wherein inorganic base is selected from group consisting of sodium methoxide, sodium ethoxide, sodium carbonate, potassium hydroxide, potassium carbonate, potassium tert-butoxide, potassium methoxide, and potassium ethoxide.

3) The process as claimed in claim 1, wherein the catalyst is selected from tetra butyl ammonium bromide, tetra propyl ammonium bromide, tri butyl benzyl ammonium bromide, tetra octyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulphate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide, ethyl triphenyl phosphonium bromide more preferably tetra butyl ammonium bromide or alkyl iodides like sodium iodide, potassium iodide and lithium iodide.

4) The process as claimed in claim 1, wherein solvent is selected from water, ketonic solvent selected form acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl amyl ketone, cyclohexanone, di isobutyl ketone, acetophenone, butanone, ethyl isopropyl ketone; alcoholic solvent selected from methanol, ethanol, isopropanol, n-butanol, glycerol, tert-butyl alcohol, 2-pentanol, propylene glycol and chlorinated solvent selected from dichloromethane, dichloroethane, carbon tetrachloride, perchloromethane, and vinyl chloride.

5) The process as claimed in claim 1, wherein acid is selected from acetic acid, sulfuric acid, and hydrochloric acid.

6) The process as claimed in claim 1, wherein solvent used for the preparation of compound of formula (IV), formula (VIII) is ketonic solvent and for compound of formula (I) is alcoholic solvent.

7) The compound of formula (I) obtained by the process as claimed in claim 1, is free from process impurities of formula (IV-a), formula (VIII-a), formula (I-a) and formula (I-b); and a compound of formula (VI).


8) The process as claimed in claim 1, wherein compound of formula (IV) and compound of formula (VIII) is substantially pure having purity more than 96%.

9) The process as claimed in claim 1, wherein compound of formula (IV) and compound of formula (VIII) is substantially pure having purity more than 99%.