Title of Invention

AN IMPROVED PROCESS FOR PREPARATION OF LOSARTAN POTASSIUM IN CRYSTALLINE FORM-1

Abstract An improved process for the preparation of Form-I of Losartan potassium, which comprises: (a) reacting Losartan free acid of formula (II) with potassium hydroxide in first organic solvent below 50oC to obtain in-situ Losartan potassium of formula (I); (b) adding second organic solvent (c) isolating crystalline Losartan Potassium form-I.
Full Text FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
"AN IMPROVED PROCESS FOR PREPARATION OF LOSARTAN POTASSIUM IN CRYSTALLINE FORM -1"
We, CADELA HEALTHCARE LIMITED, a company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Road, Ahmedabad-380015, Gujarat, India.
The following specification describes the invention:
1

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of losartan and its pharmaceutically acceptable salt like losartan potassium. Losartan potassium is chemically known as 2-butyl-4-chloro-l-[p-(0-lH-tetrazole-5-yl-phenyl)benzyl]imidazole-5-methanol monopotassium (which is hereinafter referred to using the adopted name "losartan potassium" having the Formula I. The present invention further relates to the a novel process for preparation of crystalline Losartan Potassium Form -1.

BACKGROUND OF THE INVENTION
Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.
Losartan potassium, also known as 2-butyl-4-chloro-l-[p-(o-lH-tetrazole-5-yl-phenyl) benzyl] imidazole-5-methanol monopotassium salt, is a competitive AT1 angiotensin II receptor antagonist and is commercially available in pharmaceutical products sold using the trademark COZAAR™. See, e.g. The Merck Index, Thirteenth Edition, 2001, p. 1000, monograph 5604; and Physician's Desk Reference, "Cozarar," 58th Edition, pp. 1952-1957 (2004).
It is known in the art to synthesize Losartan Potassium from the acid form of Losartan. Losartan Potassium (Shown as the compound of Formula (I) above) is known in the art is synthesized by reacting its acid (Shown as the compound of Formula (II) above) with KOH. The intermediate acid Formula (II) in turn is synthesized by detritylation of 2-n-butyl-4-chloro-5-hydroxymethyl-l-[((2’-triphenylmethyltetrazole-5-yl)biphenyl-4-yl)-methyl] imidazole (shown as the compound of formula (III) below)
2


The synthesis of Trityl Losartan (the reactant of Formula (III) above) is known in the art. See J. Med. Chem., 34, 2525-2527 (1991); J. Org. Chem., 59, 6391-6394 (1994); US 5,138,069. Trityl Losartan (and the Losartan acid/free Losartan) and may alternatively be prepared using the reactions and techniques described in US Patent No. 5,138,069 and patent application number WO93/10106.
The preparation of Trityl Losartan of Losartan acid (II) by acid-catalyzed cleavage of Trityl group from Trityl Losartan (III) is disclosed in U.S. 5,281,603. Another method disclosed to prepare Losartan acid from Trityl Losartan is disclosed in U.S. 5,281,604. In this process Trityl Losartan (III) is refluxed in a mixture of methanol and tetrahydrofuran in presence of catalytic acid like hydrochloric acid for 18 hours to get Losartan acid (II).
U.S Patent Application 2006/0020005 Al discloses the process for making Losartan free acid, an intermediate of Losartan Potassium, which is substantially free of 2-n-butyl-4-chloro-l-[[2'-tetrazole-5-yl)[l,r-biphenyl]-4-yl]-methyl]-lH-imidazole-5-methoxy methyl ether, comprising reacting of 2-n-butyl-4-chloro-5-hydroxymethyl-l-[((2'-triphenylmethyl tetrazole-5-yl)biphenyl-4-yl)-methyl] imidazole (Trityl Losartan) of Formula (III) with an aqueous acid in presence of an organic solvent to give 2-butyl-4-chloro-l-[p-(o-lH-tetrazole-
5-yl-phenyl)benzyl]imidazole-5-methanol (Losartan free acid) of Formula (II). Suitable aqueous acids include but not limited to methanesulfonic acid, triflouroacetic acid, trifluoromethanesulfonic acid, sulfuric acid, phosphoric acid, benzenesulfonic acid, p-toluenesulfonic acid, p-chlorobenzenesulfonic acid, hydrochloric acid, acetic acid, formic acid and the like.
U.S Patent Application 2006/0241161 Al discloses a method of increasing the flowability of Losartan Potassium powder initially having a Hausner ratio of about 1.45 or greater comprising the step of reslurrying the losartan potassium powder in a reslurry solvent selected from the group consisting of hydrocarbons, the alkyl ethers, the alkyl esters, and the mixtures of two or more of these.
3

U.S. Patent Application 2005/0131040 Al discloses the process for the preparation of Losartan potassium crystalline Form I or in the crystalline hydrate form having PXRD patterns with peaks at about 5.7, 8.9, 13.3, 17.5, 20.0 and 21.1±0.2 degrees 20, comprising the reaction of a dispersion of acid losartan, in an organic aprotic solvent, with a potassium basic salt, in the presence of water.
U.S. Patent Application 2004/0006237 Al discloses process for preparing losartan potassium Form I comprising the steps of:
(a) providing a solution of losartan potassium in a first solvent to form a solution, the solvent being characterized as having a boiling point of about 135°C, or below,
(b) reducing the temperature of the solution, and
(c) isolating losartan potassium Form I.
Also, provided is the process for preparing losartan potassium Form I comprising the steps of:
(a) providing a solution of losartan potassium in a first solvent to form a solution, the solvent being characterized as having a boiling point of about 135°C, or below,
(b) reducing the temperature of the solution, and
(c) adding to the solution a second solvent selected from the group consisting of ethyl acetate, toluene, acetone, methylethyl ketone, methylene chloride, acetonitrile, dimethyl carbonate, and hexane whereby a suspension is formed,
and isolating losartan potassium Form I.
WO 2005/066158 A2 discloses an improved synthesis of Losartan potassium comprising reacting approximately equimolar quantities of potassium salts such as potassium tertiary butoxide as a solution in a secondary/tertiary alcohol with Trityl Losartan in methanol. The application WO '158 A2 also discloses manufacture of polymorph Form 1 of Losartan potassium comprising treating Trityl Losartan with equimolar quantity of anhydrous potassium salts in methanol;
WO 2004/076442 Al relates to the polymorphic Form A and Form B and pharmaceutical compositions that include the Form A and Form B of Losartan Potassium and processes for preparing them. Form A and Form B are characterized by XRD and 1R bands.
WO 2002/094816 discloses the process for crystallization of Losartan potassium by reacting Trityl Losartan with potassium hydroxide in an alcohol followed by concentration under reduced pressure to remove alcohol, and adding anti-solvent to isolate Losartan Potassium.
4

WO 2005/023758 A2 discloses the process for preparation of Trityl Losartan by reacting 2-n-butyl-4-chloro-lH-imidazole-5-carboxaldehyde with N-(triphenylmethyl)-5-[4'-(bromo methyl)biphenyl-2-yl)]tetrazole in a biphasic solvent system comprising water and an
organic solvent in the presence of a base and a phase transfer catalyst at ambient temperature
to reflux temperature of the solvent for sufficient time to form an intermediate. The process also relates to detritylation in an alcoholic solvent in the absence of acid or base catalysts at ambient temperature to reflux temperature of the solvent for sufficient time to effect deprotection. Further isolating polymorph Form I by filtration after azeotropic removal of water, till water content in the mixture is reduced below 0.1%.
Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid-state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. For a general review of polymorphs and the pharmaceutical applications of polymorphs see G. M. Wall, Pharm Manuf. 3, 33 (1986); J. K. Haleblian and W. McCrone, J. Pharm. Sci., 58, 911 (1969); and J. K. Haleblian, J. Pharm. Sci, 64, 1269 (1975), all of which are incorporated herein by reference.
Thus, there is still a need to provide a cost-effective, non-hazardous, simple, efficient and industrially viable process which can overcome some common drawbacks of the prior art processes for preparing cyrstalline polymorphic Form I of Losartan potassium.
It is also an object of the present invention to provide a crystalline Form - I of Losartan Potassium by a novel process.
OBJECTS OF THE INVENTION
It is an object of the present invention in its preferred form to provide an improved process for preparation of Losartan free acid compound of formula (II) from Trityl Losartan of formula (III).
5

It is also an object of the present invention to provide an improved process for preparation of Trityl Losartan of formula (III).
It is yet another object of the present invention to provide highly pure Losartan
potassium Form I having individual impurities less than 0.1% and total impurities less than
0.5%, measured by area percentage of HPLC.
It is also an object of the present invention in its preferred form to provide an improved process for preparation of crystalline Form -1 of Losartan Potassium characterized by its x-ray powder diffraction and differential scanning calorimetry.
Further object of the present invention is to overcome the problems associated with the prior art process and to prepare Losartan Potasssium by simple, cost effective, non-hazardous and easily scaleable way.
SUMMARY OF THE INVENTION
The present invention provides an improved process for preparation of as 2-butyl-4-chloro-l-[p-(o-lH-tetrazole-5-yl-phenyl) benzyl]imidazole-5-methanol of formula (II), which is useful in the preparation of Losartan potassium or solvates, or hydrates thereof.

with potassium hydroxide in first organic solvent below 50°C to form Losartan potassium of
formula (I):

b) adding second organic solvent
6
According to the present invention, there is prpvided a process for the preparation of Losartan potassium "Form-1", which comprises the steps of a) reacting Losartan free

c) isolating Losartan Potassium Form -1
Furthermore, the present invention relates to an improved process for the preparation
of 2-n-butyl-4-chloro-5-hydroxymethyl-l-[((2'-triphenylmethyltetrazole-5-yl)biphenyl-4-yl)-
methyl] imidazole (Trityl Losartan) of formula (III);

comprising the steps of:
a) reacting 2-n-butyl-4-chloro-lH-imidazole-5-carboxaldehyde (KL-1) with N-(triphenylmethyl)-5-[4'-(bromo methyl)biphenyl-2-yl)]tetrazole in a mixture of water immiscible organic solvent and water in presence of inorganic base and phase transfer catalyst at ambient temperature to reflux temperature of the solvent for sufficient time to form an intermediate;
b) separating the layers and reducing the intermediate in organic layer with solution of sodium borohydride in S.D.S (Special Denatured Spirit) at 25°C to 40°C for 2-3 hours;
c) adjusting the pH of the reaction mass with dilute acetic acid;
d) separating the layers and washing the organic layer with water at 25°C to 40°C;
e) separating the layers and distilling the organic layer by hot water circulation below 80°C and adding second organic solvent at about 70°C to 80°C;
f) cooling the reaction mixture to about 5°C to 10°C followed by filtration and washing with organic solvent;
g) optionally crystallizing the Trityl Losartan of formula (III) with suitable organic solvent
h) isolating Trityl Losartan of formula (III)
Furthermore, the present invention relates to an improved process for the preparation of as 2-butyl-4-chloro-1 -[p-(o-1 H-tetrazole-5-yl-phenyl)benzyl]imidazole-5-methanol (Losartan free acid) of formula (II);
7


comprising the steps of:
a) reacting the compound of formula (III)

with an aqueous acid in a aprotic polar solvent in presence of base at an ambient temperature to reflux temperature of the solvent for sufficient amount of time to effect deprotection;
b) filtering the isolated intermediate thus obtained followed by washing with mixture of
aprotic polar solvent and water;
c) treating the above filtrate of step (b) with aprotic polar solvent;
d) adjusting the pH 5.0-5.5 of the solution with dilute acetic acid;
e) filtering the product followed by washing with water;
f) treating the wet-cake with aprotic polar solvent at about 75°C to 82°C;
g) cooling the reaction mixture to about 30°C to 40°C followed by filtration and washing with aprotic polar solvent;
h) optionally crystallizing the Losartan free acid of formula (II) with suitable organic
solvent; and i) isolating Losartan free acid of formula (II)
According to another aspect of the present invention there is provided a crystalline Form-I of Losartan potassium in its preferred form characterized an endothermic maximum of conversion at an extrapolated onset temperature of 229.5°C and an endothermic maximum of melting at an extrapolated onset temperature of 273.2°C, when heated in an open pan in a differential scanning calorimetric cell at a rate of 10°C/min under a nitrogen atmosphere and
8

an X-ray powder diffraction patter having 7.24, 11.02, 14.16, 15.07, 18.46, 18.87, 26.53, 27.30, 29.15±0.2° as the characteristic peaks.
According to yet another aspect of the present invention Form I of Losartan potassium is further characterized by FTIR spectra from 4000 cm-1 to 600 cm-1 having spectral absorbances: 764, 713, 886, 934, 953, 1358, 1340 cm1.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. I is an FTIR spectra of Losartan potassium Form - I from 4000 cm-1 to 600 cm-1.
FIG. II is an X-ray powder diffractogram (XRD) of the Form - I of Losartan Potassium measured on Rigaku D/Max-2200/PC Diffractometer with Cu K alpha-1 radiation source. DESCRIPTION OF THE INVENTION
According to the present invention, there is provided an improved process for the preparation of Form I of Losartan Potassium which comprises: a) reacting Losartan free acid of formula (II)



with potassium hydroxide in first organic solvent below 50°C to obtain in-situ Losartan


potassium of formula (I);





b) adding second organic solvent
c) isolating crystalline Losartan Potassium Form -1
According to the yet another preferred embodiment of the present invention, there is provided an improved process for the preparation of 2-n-butyl-4-chloro-5-hydroxymethyl-l-[((2'-triphenylmethyltetrazole-5-yl)biphenyl-4-yl)-methyl] imidazole (Trityl Losartan) of formula (III);
9


comprising the steps of:
a) reacting 2-n-butyl-4-chloro-lH-imidazole-5-carboxaldehyde (KL-1) with N-(triphenylmethyl)-5-[4'-(bromo methyl)biphenyl-2-yl)]tetrazole (KL-2) in a mixture of water immiscible organic solvent and water in presence of inorganic base and phase transfer catalyst at ambient temperature to reflux temperature of the solvent for sufficient time to form an intermediate;
b) separating the layers and reducing the intermediate in organic layer with solution of sodium borohydride in S.D.S (Special Denatured Spirit) at 25°C to 40°C for 2-3 hours;
c) adjusting the pH of the reaction mass with dilute acetic acid;
d) separating the layers and washing the organic layer with water at 25°C to 40°C;
e) separating the layers and distilling the organic layer by hot water circulation below 80°C and adding second organic solvent at about 70°C to 80°C;
f) cooling the reaction mixture to about 5°C to 10°C followed by filtration and washing with organic solvent;
g) optionally crystallizing the Trityl Losartan of formula (III) with suitable organic solvent; and
h) isolating Trityl Losartan of formula (III)
10
According to the yet another preferred embodiment of the present invention, there is provided an improved process for the preparation of as 2-butyl-4-chloro-l-[p-(o-lH-tetrazole-5-yl-phenyl)benzyl]imidazole-5-methanol (Losartan free acid) of formula (II);


comprising the steps of:
a) reacting the compound of formula (III)

with an aqueous acid in a aprotic polar solvent in presence of base at an ambient temperature to reflux temperature of the solvent for sufficient amount of time to effect deprotection;
b) filtering the isolated intermediate thus obtained followed by washing with mixture of aprotic polar solvent and water;
c) treating the above filtrate of step (b) with aprotic polar solvent;
d) adjusting the pH 5.0-5.5 of the solution with dilute acetic acid;
e) filtering the product followed by washing with water;
f) treating the wet-cake with aprotic polar solvent at about 75°C to 82°C;
g) cooling the reaction mixture to about 30°C to 40°C followed by filtration and washing
with aprotic polar solvent;
h) optionally crystallizing the Losartan free acid of formula (II) with suitable organic
solvent; and
j) isolating Losartan free acid of formula (II)
According to one of the important aspect of the present invention the first organic solvent can be selected from the group of C1-C4 alcohol, ketones, esters, hydrocarbons, amides etc. preferably C1-C4 alcohol, most preferably ethanol. The second organic solvent can be selected from the group ethyl acetate, toluene, acetone, methylethyl ketone, methylene chloride, acetonitrile, dimethyl carbonate, diisopropyl ether and hexane, preferably diisopropyl ether.
According to the most preferred embodiment of the present invention for the preparation of compound of formula (III) i.e. Trityl Losartan, the water immiscible organic solvent can be selected from the group of hydrocarbons, acetates, halogenated hydrocarbons, ethers etc, preferably toluene in presence of inorganic base like alkali metal hydroxide, carbonates, bicarbonates i.e. sodium hydroxide, potassium hydroxide, sodium carbonate or
potassium carbonate or bicarbonates etc, preferably sodium hydroxide.
11

The phase transfer catalyst used can be selected from the group consisting of tetrabutyl ammonium bromide, tetrabutyl ammonium chloride, triethylbenzyl ammonium bromide, triethyl benzylammonium chloride, tetrabutyl ammonium iodide, preferably tetrabutyl ammonium iodide.
The reaction is performed as an ambient temperature to reflux temperature of solvent i.e. from 20°C to about 100°C, preferably at 80°C to 90°C. The washing in the step (f) is performed with suitable organic solvent like toluene, methylene dichloride, ethyl acetate or mixture thereof optionally with water, preferably ethyl acetate.
According to still further aspect of the present invention the crystallization of Trityl Losartan of formula (III) in step (g) can be performed by using suitable organic solvent, but not limited to, members from the classes: ketonic solvents such as acetone, ethylmethyl ketone, methyl isobutyl ketone and the like; ether solvents such as diethyl ether, dimethyl ether, di-isoopropyl ether, methyltertiarybutyl ether, tetrahydrofuran, 1,4-dioxane and the like; hydrocarbon solvents such as toluene, xylene and the like; nitrile solvents such as acetonitrile, propionitrile and the like; halogenated solvents such as dichloromethane, 1,2-dichloromethane, chloroform, carbon tetrachloride and the like; aprotic polar solvents such as dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide and the like; or mixtures of any two or more thereof in various proportions, preferably acetonitrile.
According to the still preferred embodiment of the present invention, in the preparation of 2-butyl-4-chloro-1 -[p-(o-1-H-tetrazole-5-yl-phenyl)benzyl]imidazole-5-methanol (Losartan free acid) of formula (II) the aqueous acid in step (a) includes but not limited to methanesulfonic acid, triflouroacetic acid, trifluoromethanesulfonic acid, sulfuric acid, phosphoric acid, benzenesulfonic acid, p-toluenesulfonic acid, p-chlorobenzenesulfonic acid, hydrochloric acid, acetic acid, formic acid and the like, preferably sulfuric acid.
The aprotic polar solvent includes but is not limited to acetonitrile, tetrahydrofuran, dimethyl foramide, dimethyl sulfoxide etc, preferably acetonitrile. The reaction is proceeded in presence of a base like sodium or potassium hydroxide preferably sodium hydroxide at an ambient temperature to reflux temperature of the solvent i.e. from about 10°C to about 40°C. The washing in step (b) is performed by using mixture of acetonitrile and water followed by further treatment with acetonitrile in step (c). The wet-cake in step (f) is treated again with acetonitrile and washed with the same in step (g).
According to still further aspect of the present invention the crystallization of Losartan free acid of formula (II) in step (h) can be performed by using suitable organic solvent, but not limited to, members from the classes: ketonic solvents such as acetone,
12

ethylmethyl ketone, methyl isobutyl ketone and the like; ether solvents such as diethyl ether, dimethyl ether, di-isoopropyl ether, methyltertiarybutyl ether, tetrahydrofuran, 1,4-dioxane and the like; hydrocarbon solvents such as toluene, xylene and the like; nitrile solvents such as acetonitrile, propionitrile and the like; halogenated solvents such as dichloromethane, 1,2-dichloromethane, chloroform, carbon tetrachloride and the like; aprotic polar solvents such as dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide and the like; or mixtures of any two or more thereof in various proportions.
According to further aspect of the present invention there is provided a crystalline Form-I of Losartan potassium in its preferred form characterized an endothermic maximum of conversion at an extrapolated onset temperature of 229.5°C and an endothermic maximum of melting at an extrapolated onset temperature of 273.2°C, when heated in an open pan in a differential scanning calorimetric cell at a rate of 10°C/min under a nitrogen atmosphere and an X-ray powder diffraction patter having 7.24, 11.02, 14.16, 15.07, 18.46, 18.87, 26.53, 27.30, 29.15±0.2° as the characteristic peaks.
According to still further aspect of the present invention Form I of Losartan potassium is further characterized by FTIR spectra from 4000 cm-1 to 600 cm-1 having spectral absorbances: 764, 713, 886, 934, 953,1358,1340 cm-1.
According to the present invention, process for preparing Losartan potassium is represented in below mentioned Scheme-1.



The most preferred embodiment of the present invention is to prepare crystalline Losartan Potassium Form - I having purity greater than or equal to 99.5% by HPLC and having all the single individual impurities not more than 0.1% and the total impurities not more than 1.0%.
It is one of the preferred embodiments of the present invention to provide process for preparation of Losartan potassium having mean particle size less than 400 fan, preferably less than 200 pm and more preferably less than 100 //m when measured with Malvern light scattering instruments.
Although the invention has been described with reference to a specific example, it will be appreciated by those skilled in the art that the invention may be embodied in many other forms.
The process of the present invention will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be constructed as limit to the scope of the claims in any manner.
Examples
Example-1: Preparation of Trityl Losartan Formula (III):
To a solution of N-(triphenylmethyl)-5-4'-(bromomethyl)biphenyl-2-yl]tetrazole [1.0 Kg; 1.61mol] (KL-2), 2-n-butyl-4-chloro-lH-imidazol-5-carboxaldehyde [0.28 kg; 1.501 mol] (KL-1) and tetra butyl ammonium bromide [0.01 kg; 0.03mol] in 5L, toluene is added 0.6 L of a 3 M solution of sodium hydroxide in water. The reaction is vigorously stirred and
refluxed for 3.5 hour at 80°C to 90°C. The progress of the reaction is monitored by HPLC. The reaction mass is cooled to room temperature and is allowed to settle. The tower aqueous
layer is discarded and the toluene layer is washed with water (2 L). The toluene layer is
14

treated with solution of sodium borohydride (0.027 kg, 0.729 mol) in special denatured spirit 1.20 L at 35°C to 45°C is added slowly. Progress of the reaction is monitored by HPLC. The pH of the reaction mass is adjusted with dilute acetic acid from 7.0 to 7.2. The layers were
separated and organic layer was washed with water. The toluene was distilled under vacuum
below 80°C and the resulting residue was treated with ethyl acetate at 70°C to 80°C, filtered
and washed with ethyl acetate and dried at 50°C to 60°C.
IH NMR(CDO.: # 9. 73 (S,1F1,) ; 7.92 (m,l 1-1) ; 7.51-6. 81 (m, 22H); 5.45 (s, 2H); 2.49
(t,2H); 1.64 (q, 21-1); 1.28 (sextet, 2H) and 0.86 (t, 3H)
Example-2: Preparation of Trityl Losartan Formula (II):
Trityl losartan (1.0 Kg), 0.375 Kg of sulfuric acid and 2.4 L of water were taken in RBF. 2.6 L of acetonitrile was added to the above reaction mass at an ambient temperature. The above reaction mass is slowly dumped into the freshly prepared sodium hydroxide solution at 10°C to 20° and the reaction mass is stirred for 30 minutes. 0.05 Kg of activated charcoal is added. The reaction mass is filtered through Hyflosupercel bed and washed with acetonitrile and water mixture. The filtrate is treated with acetonitrile in RBF at 15°C to 35°C. The pH of the reaction mass was adjusted to 5.0 to 5.5 by adding dilute acetic acid. The product thus obtained was filtered and washed with water. The wet-cake were taken in acetonitrile in RBF and refluxed to about 75°C to 82°C for 2 to 3 hours. The reaction mixture is cooled to about 30°C to about 40°C. Filtered and washed with acetonitrile and dried at 70°C to 80°C to obtain Losartan free acid.
Example-3: Preparation of crystalline Losartan potassium Form-I
Potassium hydroxide (0.11 Kg) and ethanol (3.20 L) were taken in RBF. The reaction mixture was stirred to dissolve completely at about 20°C to 40°C. Losartan free acid (0.080 Kg) prepared as above as added to the clear solution and further stirred to ensure clear solution as at about 20°C to 40°C. Activated charcoal was added to the reaction mixture. After obtaining the clear solution, the reaction mass was treated with diisopropyl ether (17.60 L) at 20°C to 40°C and stirred for 2 to 2.5 hours and reaction was monitored by HPLC. The precipitated product was filtered and washed with diisopropyl ether. The product-was dried/at


70°C to 80°C to obtain crystalline Losartan Form-I.

Dated this the 22nd day of January 2007
15

Documents:

148-mum-2007-abstract(21-1-2008).pdf

148-MUM-2007-CLAIMS(AMENDED)-(1-1-2014).pdf

148-mum-2007-claims(complete)-(21-1-2008).pdf

148-MUM-2007-CLAIMS(MARKED COPY)-(1-1-2014).pdf

148-MUM-2007-CORRESPONDENCE(15-12-2010).pdf

148-mum-2007-correspondence(21-1-2008).pdf

148-MUM-2007-CORRESPONDENCE(23-12-2013).pdf

148-MUM-2007-CORRESPONDENCE(7-1-2014).pdf

148-MUM-2007-CORRESPONDENCE(8-2-2013).pdf

148-mum-2007-correspondence-received.pdf

148-mum-2007-description (provisional).pdf

148-mum-2007-description(complete)-(21-1-2008).pdf

148-mum-2007-drawing(21-1-2008).pdf

148-mum-2007-drawings.pdf

148-mum-2007-form 1(7-5-2007).pdf

148-MUM-2007-FORM 18(15-12-2010).pdf

148-mum-2007-form 2(complete)-(21-1-2008).pdf

148-mum-2007-form 2(title page)-(complete)-(21-1-2008).pdf

148-mum-2007-form 3(25-1-2007).pdf

148-mum-2007-form 5(21-1-2008).pdf

148-mum-2007-form-1.pdf

148-mum-2007-form-2.doc

148-mum-2007-form-2.pdf

148-MUM-2007-GENERAL POWER OF ATTORNEY(23-12-2013).pdf

148-MUM-2007-REPLY TO EXAMINATION REPORT(1-1-2014).pdf

abstract1.jpg


Patent Number 259226
Indian Patent Application Number 148/MUM/2007
PG Journal Number 10/2014
Publication Date 07-Mar-2014
Grant Date 04-Mar-2014
Date of Filing 25-Jan-2007
Name of Patentee CADILA HEALTHCARE LIMITED
Applicant Address ZYDUS TOWER, SATELLITE CROSS ROAD, AHMEDABAD-380015,
Inventors:
# Inventor's Name Inventor's Address
1 ROY, RUSHIKESH UDAYKUMAR ZYDUS TOWER, SATELLITE CROSS ROAD, AHMEDABAD-380015,
2 DWIVEDI ,SHRIPRAKASH DHAR ZYDUS TOWER,SATRLLITE CROSS ROAD, AHMEDABAD-380015,
PCT International Classification Number C07D403/10
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA