FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
IMPROVED AND ENVIRONMENT FRIENDLY PREPARATION PROCESS FOR LOSARTAN POTASSIUM
UNICHEM LABORATORIES LIMITED, A COMPANY REGISTERED UNDER THE INDIAN COMPANY ACT, 1956, HAVING ITS REGISTERED OFFICE LOCATED AT UNICHEM BHAVAN, PRABHAT ESTATE, S.V.ROAD, JOGESHWARI (W), MUMBAI 400 102, MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed.
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IMPROVED AND ENVIRONMENT FRIENDLY PREPARATION PROCESS FOR LOSARTAN POTASSIUM
TECHNICAL FIELD
The present invention relates to an improved process for the preparation of angiotensin II receptor antagonists.
BACKGROUND OF THE INVENTION
2-Butyl-4-chloro-l-[[2'-(lH-tetrazol-5-yl) l,l'-biphenyl]-4-yl] methyl]-lH-imidazole-5 methanol mono potassium salt having formula I commonly known as Losartan potassium. Losartan potassium (David J.C. et al, US 5138069) is an angiotensin II (All) inhibitor useful in the treatment of angiotensin-dependent hypertension. Losartan potassium is also useful in the treatment of hypercholesterolemia, as it decreases total cholesterol.


HOH2C

(I)
Several methods for the preparation of Losartan Potassium are reported in the literature. Also, several methods are reported in literature for the synthesis of Losartan Potassium starting from Losartan free acid of formula (II).
Losartan Potassium also exhibits polymorphism. Several polymophic forms have been prepared and characterized.
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EP0324377 (David J.C) disclosed a process wherein a solution of aqueous potassium hydroxide was added to a Losartan free acid suspension in isopropyl alcohol. After removal of water, heptane was added to the reaction mixture in isopropyl alcohol and it is stirred. The product thus obtained was collected by filtration. The disadvantage of the above method is the removal of water from the reaction mixture which is time consuming and the recovered isopropyl alcohol can not be recycled.
US 5,608,075 also describe a process wherein the Losartan Potassium was synthesized by a method in which the Losartan free acid was treated with aqueous potassium hydroxide solution at room temperature . The aqueous solution thus obtained was added to the refluxing mixture of isopropyl alcohol and cyclohexane and the water was removed by azeotropic distillation. Here also, the disadvantage of the process is of removal of water from the reaction mixture which is again very time consuming and the recovered solvent obtained as a mixture which can not be recycled.
Therefore there exist a need in order to improve the efficiency of the process which eliminates the disadvantages of the prior art reported process for the synthesis of Losartan Potassium.
OBJECT OF THE INVENTION
The object of the present invention is to provide a simpler process for the synthesis of Losartan Potassium.
Another object of the present invention is to provide a Losartan potassium with a good yield and purity.
Another object of the present invention is to provide an efficient and ecofriendly process for the synthesis of Losartan Potassium.
SUMMARY OF THE INVENTION
According to the present invention there is provided a process for the preparation of Losartan Potassium of formula (I),
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which comprises
a. reaction of Losartan free acid of formula (II) with an aqueous solution of
potassium hydroxide
b. addition of aqueous reaction mass to water immiscible solvent.
c. azeotropic distillation to get the Losartan Potassium of formula (I)
Also, according to the present invention a process for preparation of Losartan Potassium of formula (I) comprises
a. reaction of Losartan free acid of formula (II) with an aqueous solution of
potassium hydroxide
b. addition of aqueous reaction mass to water immiscible solvent.
c. azeotropic distillation to remove water at desired level
d. distill the resultant reaction mass partially or completely
e. addition of other solvent to resultant mixture to get the Losartan Potassium of
formula (I) after filtration.
DETAILED DESCRIPTION OF THE INVENTION
According to the present invention there is provided a process for manufacture of Losartan potassium of formula (I).
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Aqueous KOH Heptane

(I)

The object of the present invention is to provide an improved , more efficient and environmentally friendly method for the synthesis of the Losartan Potassium.
According to the present aspect of the invention a process for manufacture of Losartan potassium avoids the use of mixing of the solvents used to remove water from the reaction mixture and hence avoids the wastage of solvents as well as reduce the reaction time .
According to the present invention the solvent which is used to remove water can be recycled into the system by separating water azeotropically.
Typically the Losartan potassium is prepared by adding Losartan free acid of formula (II) in aqueous solution of potassium hydroxide . The suspension thus obtained is stirred at 20 to 50°C, preferably at 30-35°C . The obtained mixture is filtered to remove any insoluble material or particle so as to get the clear filtrate. The clear solution thus obtained is slowly added to the refluxing heptane . The water present in the mixture is removed by azeotropic distillation using Dean and Stark. The lower water layer is removed simultaneously and the upper heptane layer is recycled into the system. The distillation is continued till the moisture content is less than 0.04%. After the desired moisture content i.e. less than 0.04%. was achieved the mixture was cooled to room temperature, stirred and filtered to get Losartan Potassium.
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In another aspect of the present invention any water immiscible solvent like aliphatic hydrocarbon ,aromatic hydrocarbon, chlorinated hydrocarbon ,ester or ketone is used to remove water azeotropically. Thus, the solvent like heptane , hexane, cyclohexane, toluene, dichloromethane , n-butanol, ethyl acetate or methylisobutyl ketone is used to remove water azeotropically
In another aspect of the present invention , after the desired level of water content is achieved , the remaining heptane was removed completely and other solvent like propanol, butanol, methanol, acetone, ethylacetate is added , and the mixture thus obtained is stirred at room temperature and filtered to get Losartan Potassium.
Yet another embodiment of the present invention after complete removal of water i.e. after achieving desired level of moisture content, the remaining heptane was distilled partially and to the resulting reaction mass, other solvents like propanol, butanol, ethylacetate , acetone, methylisobutyl ketone is added, and stirred at room temperature to refluxing . The mixture was cooled and filtered to get Losartan Potassium.
Losartan free acid of formula (II) is prepared using reaction and technique described in EP 0324377 and US 5,138,069.
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.
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Example I
To an aqueous solution of potassium hydroxide (6.04 gm in 200 ml water) was added Losartan free acid (40.0 gm). The resulting mixture was stirred at 30-35°C for 30 mints. The resulting mixture was filtered to get clear solution. The obtained clear solution was added to the refluxing heptane (1.0 liter) . The reaction mass was distilled azeotropically to remove water by using Dean and Stark. After required quantity of water was removed, the moisture content was checked. When moisture content of 0.03% was achieved, the mixture was cooled to room temperature and filtered. The material thus obtained was dried to get Losartan Potassium.(40.4 gm)., yield 92.6% and purity 99.6%.
Example-2
A solution of potassium hydroxide (7.56gm) was prepared in water (150 ml) under stirring at room temperature. To this solution Losartan free acid (50.0gm) was added and stirred for 30-40 mints 30-35°C. The resulting solution was filtered and the clear filtrate was slowly added to the refluxing heptane (500.0 ml). From the resulting mixture water was removed azeotropically by using Dean and Stark. After complete removal of water (Moisture content 0.023%), the heptane was distilled completely . To the residue thus obtained isopropyl alcohol (150 ml) was added and the mixture was stirred at room temperature. It was filtered and dried to get Losartan potassium (43.6 gm) Yield 80.0 % and purity 99.65%
Example-3
To an aqueous solution of potassium hydroxide (1.51 gm in 50 ml water) was added Losartan free acid (10.0 gm). The resulting mixture was stirred at 30-35°C for 30 mints. The resulting solution was filtered and the clear filtrate was slowly added to the refluxing heptane (250.0 ml) . The reaction mass thus obtained was distilled azeotropically to remove water by using Dean and Stark. After the required quantity of water was removed , and when moisture content of less than 0.03% was achieved ,the heptane was distilled till approximately 50.0 ml was left in reaction mass. To the reaction
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mass thus obtained isopropyl alcohol (50.0ml) was added and cooled to room temperature . It was filtered and dried to get Losartan Potassium (7.9 gm), yield 73.8% and purity 99.78%
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We Claim:
1. A process for preparation of Losartan Potassium of formula (I)

which comprises
a. reaction of Losartan free acid of formula (II) with an aqueous solution of
potassium hydroxide
b. addition of aqueous reaction mass to water immiscible solvent.
c. azeotropic distillation to get the Losartan Potassium of formula (I)
2. A process of claim l, wherein potassium hydroxide used is, in the range of 0.9 to 1.1 mole , preferably 1 mole with respect to Losartan free acid.
3. A process of claim l, wherein Losartan free acid of formula (II) reacted with an aqueous solution of potassium hydroxide at 20 to 50°C, preferably at 30-3 5°C.
4. A process of claim l, wherein the water immiscible solvent used are like heptane , hexane, cyclohexane, toluene, dichloromethane , n-butanol, ethyl acetate or methylisobutyl ketone.
5. A process for preparation of Losartan Potassium of formula (I) which comprises
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a. reaction of Losartan free acid of formula (II) with an aqueous solution of
potassium hydroxide
b. addition of aqueous reaction mass to water immiscible solvent.
c. azeotropic distillation to remove water at desired level
d. distill the solvent used to remove water completely or partially to get
Losartan potassium.
e. addition of other solvent to resultant mass to get the Losartan Potassium
of formula (I) after filtration.
6. A process of claim-5, wherein the water immiscible solvents used in b are like heptane , hexane, cyclohexane , toluene, dichloromethane , n-butanol, ethyl acetate or methylisobutyl ketone.
7. A process of claim-5, wherein the water immiscible solvents used in e are like propanol, butanol, acetone , ethyl acetate and toluene
8. A process for the preparation of compounds of formula (I) substantially as herein described and illustrated with reference to the accompanying examples.
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ABSTRACT:
The present invention provides an environment friendly process for making Losartan Potassium. According to the present invention , to the Losartan free acid , aqueous potassium hydroxide solution is added . The mixture is stirred, and the filtrate is added to the water immiscible solvent. The water was removed azeotropically to form Losartan potassium.
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