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 THE PREPARATION OF 2-
BUTYL-4-CHLORO-l-[[(2,-(lH - TETRAZOLE-5-YL)[l,l'-BIPHENYL]-4-YL] METHYL]- 1H-IMIDAZOLE-5-METHANOL"
We, CADILA 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:

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of 2-butyl-4-chloro-l-[[(2'-(lH-tetrazole-5-yl)[1,1-biphenyl]-4-yl]methyl]-lH-imidazole-5-methanol, particularly to an improved process for the preparation of 2-butyl-4-chloro-l-[[(2'-(lH-tetrazole-5-yl)[1,1'-biphenyl]-4-yl]methyl]-lH-imidazole-5-methanol monopotassium salt useful as an antihypertensive agent.
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, chemically known as 2-butyl-4-chloro-l-[[(2'-(lH-tetrazole-5-yl)[1,1-biphenyl]-4-yl]methyl]-lH-imidazole-5-methanol monopotassium (which is hereinafter referred to using the adopted name "losartan potassium" having the formula (F), 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, "Cozaar," 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 (F) above) is known in the art is synthesized by reacting its acid with KOH. The losartan acid of formula (I), is in turn synthesized by detritylAT1on of 2-n-butyl-4-chloro-5-hydroxymethyl-l-[((2'-triphenylmethyl- tetrazole-5-yl)biphenyl-4-yl)-methyl] imidazole as one of the method.
U.S Patent ApplicAT1on 2006/0211866 Al discloses a process for the preparAT1on of a biphenyl-containing compound of general formula 1:


which comprises reacting a compound of general formula II:
with a compound of general formula III:
wherein Z is a leaving group in a biphasic solvent system and in the presence of a phase
transfer catalyst.

The patent applicAT1on includes biphenyl compounds like Candesartan, Losartan, Valsartan, Irbesartan and Telmisartan as the scope of the claims. However, discloses only the process for preparAT1on of Telmisartan.
U.S Patent ApplicAT1on 2006/0241161 Al discloses a method of increasing the flowability of Losartan Potassium powder initially having a Hausner rAT1o 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.
U.S. Patent ApplicAT1on 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) isolAT1ng 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 isolAT1ng losartan potassium Form I.
WO 2002/094816 discloses the process for crystallizAT1on of Losartan potassium by reacting Trityl Losartan with potassium hydroxide in an alcohol followed by concentrAT1on under reduced pressure to remove alcohol, and adding anti-solvent to isolate Losartan Potassium.

WO 2005/014602 describes the process for the preparAT1on of losartan comprises the reaction of 4'-bromomethyl-2-cyanobiphenyl (Bromo OTBN) of the formula 3 with 2-n-butyl-4-chloro-5-formylimidazole (BCFI) of the formula of 4 in the presence of potassium carbonate and acetonitrile to give "cyano aldehyde" of the formula 5. The cyano aldehyde of the formula 5 is reduced with sodium borohydride to get "cyano alcohol" of the formula 6. The cyano alcohol is reacted with diethyl aluminium azide in the presence of triethylaluminium to give losartan of the formula 1. (Scheme-1)




n-Bu
K2CO3
CH3CN
n-Bu
(Et2AICI + NaN3)
*-
CN 1)AIEt3 2) Et2AIN3
Cyano alcohol
Cyano aldehyde

Cyano aldehyde

Losartan

Scheme-1
WO 2007/026375 Al discloses the process for the preparAT1on of losartan comprises of reacting 4'-bromomethyl-biphenyl-2-carbonitrile and 2-butyl-5-chloro-3//-imidazole-4-carbaldehyde in the presence of base and a phase transfer catalyst to get cyano aldehyde and further cyano aldehyde react with sodium azide in the presence of tributyl tin chloride in an aromAT1c solvent to form tetrazole derivAT1ve. The aldehyde group in tetrazole derivAT1ve is further reduced with sodium borohydride to give Losartan, which is converted to its potassium salt.

WO 2007/020654 Al discloses the process for the preparAT1on of Losartan potassium as shown below in scheme-2. According to the process claimed in WO '654 Al, Losartan potassium is prepared by condensing bromo OTBN (3) with BCFI (4) in presence of base to give cyano aldehyde, which is reduced to cyano alcohol by treAT1ng with sodium borohydride.
,CI
N w
7 V
H
.CI
N-/
Sodium Azide/TEA.HCI
i
N-Methyl pyrrolidinone 75%

Cyano alcohol Losartan 1
Losartan Losartan Potassium
KOH
87.15%
CHO

Scheme-2
The resulting cyano alcohol was treated with sodium azide and triethyl amine hydrochloride in a polar aprotic solvent such as DMF, DMSO, DMI (dimethyl imidazolidinone) and dimethyl acetamide, preferably N-methyl pyrrolidinone to form Losartan and it's converted into Losartan potassium by using potassium hydroxide.
CN 1915990 A discloses the process for the preparAT1on of the Losartan by condensAT1on of 4'-bromomethyl-biphenyl-2-carbonitrile and 2-butyl-5-chloro-3i/-imidazole-4-carbaldehyde (formula 4) followed by tetrazole formAT1on with sodium azide as shown in reaction scheme-3. The alternAT1ve route is also provided i.e. by reduction of aldehyde (formula 3) to 2-butyl-5-chloro-3//-imidazole-4-carbaldehyde (formula 4) with NaBEU or KBH4 followed by condensAT1on with 4'-bromomethyl-biphenyl-2-carbonitrile (Scheme-4) and thereby tetrazole formAT1on (scheme-6). Also, the aldehyde of formula 3 is directly condensed with 4'-bromomethyl-biphenyl-2-carbonitrile to get compound of formula 7 which is then reduced to compound of formula 5 with NaBFL; or KBH4 and there by tetrazole formAT1on with help of sodium azide (scheme-5).

CI I
n-Bir-^M^rHn
*N^CHO H

N-/

Scheme-3



n-Bu
N /CI H

Scheme-4

P n_Bu N CHO

N P n-Bu^jL/OH

Scheme-5

NaN3

n-Bu^N^0^—
Scheme-6

WO 2007/062675 Al discloses method for preparing metal salts of Losartan comprising treAT1ng Losartan free acid with a basic metal salt in a solvent, which comprises a mixture of iso-propyl alcohol and t-butyl methyl ether.

WO 2007/119246 Al discloses condensAT1on of 2-butyl-4-chloro-5-formyl imidazole with 2-cyano-4-bromomethyl biphenyl in a biphasic solvent system of water and an aromAT1c solvent (toluene, xylene, or chlorobenzene) in presence of a base (sodium hydroxide or potassium hydroxide) and a phase transfer catalyst. Further reduction of condensed product in presence of alcohol (methanol or ethanol) and sodium borohydride converted into Losartan by treAT1ng with inorganic azide (sodium azide) and amine salt (triethyl amine hydrochloride) in an organic solvent in presence of phase transfer catalyst followed by potassium hydroxide treatment to obtain Losartan potassium.
WO 2007/133040 Al discloses the process for the preparAT1on of Losartan, which comprises the steps of reacting a nitrile compound with triethylamine hydrochloride and sodium azide in a polar organic solvent at a temperature ranging from 105 to 135°C, the polar organic solvent being selected from the group consisting of N,N-dimethylformamide, N,N-dimethyl acetamide, N-methyl-2-pyrrolidinone and dimethylsulfoxide; adding water and acetone to the resulting solution; and adjusting the pH of the resulting mixture to 2 to 5 to induce the crystallizAT1on of losartan. The process is better described as depicted in scheme-7 as shown below.

CI OH
P
JTLJ

TEA. H CI
NaN-

Losartan Scheme-7
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 applicAT1ons of polymorphs see G. M. Wall, Pharm Manuf. 3, 33 (1986); J. K. Haleblian and W. McCrone, J. Pharm. ScL, 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 process for preparing Losartan or its pharmaceutically acceptable potassium salts. OBJECTS OF THE INVENTION
It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternAT1ve.
It is an object of the present invention in its preferred form to provide an improved process for preparAT1on of Losartan free acid compound of formula (I).
It is also an object of the present invention to provide an improved process for preparAT1on of losartan potassium of formula (F) from losartan free acid of formula (I) in crystalline Form-I.
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 preparAT1on 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 provide an useful alternAT1ve to overcome the problems associated with the prior art process and to prepare Losartan Potassium by simple, cost effective, non-hazardous and easily scaleable way. SUMMARY OF THE INVENTION
According to one embodiment, the present invention provides a process for the preparAT1on of losartan of formula (I) or its pharmaceutically acceptable potassium salt thereof substantially free from regioisomer of formula (la)

comprises of:

(a) reacting 2-n-butyl-4-chloro-5-formyl imidazole (BCFI) of formula III with potassium hydroxide in suitable organic solvent to give potassium salt 2-n-butyl-4-chloro-5-formyl imidazole (BCFI) of formula IV;



CHO
CHO
(III)

(b) reacting potassium salt 2-n-butyl-4-chloro-5-formyl imidazole (BCFI) of formula IV with 4'-bromomethyl-2-cyanobiphenyl (bromo OTBN) of formula V in polar organic solvent in absence of a base and a phase transfer catalyst to give cyano aldehyde of formula VI;


00 (VI)
(c) reducing the cyano aldehyde of formula VI with reducing agent to give cyano alcohol of formula II;
CI

(d) treAT1ng the cyano alcohol of formula III with inorganic azide and amine or salt thereof in a suitable organic solvent optionally in presence of phase transfer catalyst to form Losartan of formula I: and


N-NH

(e) optionally converting Losartan of formula I to its potassium salt of the formula (I') by treAT1ng with potassium hydroxide.

According to another embodiment, the present invention provides a process for the preparAT1on of losartan of formula (I) or its pharmaceutically acceptable potassium salt thereof substantially free from regioisomer of formula (la)

N CI N-NH

comprises of:
(a) reacting 2-n-butyl-4-chloro-5-formyl imidazole (BCFI) of formula III with potassium
hydroxide in suitable organic solvent to give potassium salt 2-n-butyl-4-chloro-5-formyl
imidazole (BCFI) of formula IV;
CHO
CHO

.CI
(I") (IV)
(b) reacting potassium salt 2-n-butyl-4-chloro-5-formyl imidazole (BCFI) of formula IV with
4'-bromomethyl-2-cyanobiphenyl (bromo OTBN) of formula V in polar organic solvent in absence of a base and a phase transfer catalyst to give cyano aldehyde of formula VI;

(c) reducing the cyano aldehyde of formula VI in-situ with reducing agent to give cyano alcohol of formula II;

(d) treAT1ng the cyano alcohol of formula III with inorganic azide and amine or salt thereof in a suitable organic solvent optionally in presence of phase transfer catalyst to form Losartan of formula I; and
.CI


(e) optionally converting Losartan of formula I to its potassium salt of the formula (I') by treAT1ng with potassium hydroxide.


According to another embodiment, the present invention provides a process for the preparAT1on of losartan of formula (I) or its pharmaceutically acceptable potassium salt thereof substantially free from regioisomer of formula (la),


(I) li. ^ (la)
comprises of:
(a) brominAT1ng OTBN of formula V with a suitable brominAT1ng agent to obtain bromo
OTBN of formula V;
(V)
Br H3C


(b) reacting 2-n-butyl-4-chloro-5-formyl imidazole (BCFI) of formula III with potassium hydroxide in suitable organic solvent to give potassium salt 2-n-butyl-4-chloro-5-formyl imidazole (BCFI) of formula IV;
CHO
CHO

.CI .CI
(III) (IV)
(c) reacting potassium salt 2-n-butyl-4-chloro-5-formyl imidazole (BCFI) of formula IV of
step (b) with 4'-bromomethyl-2-cyanobiphenyl (bromo OTBN) of formula V of step (a) in polar organic solvent in absence of a base and a phase transfer catalyst to give cyano aldehyde of formula VI;

(d) reducing the cyano aldehyde of formula VI in situ with reducing agent to give cyano alcohol of formula II;

(e) treAT1ng the cyano alcohol of formula II with inorganic azide and amine or salt thereof in
a suitable organic solvent optionally in presence of phase transfer catalyst to form
Losartan of formula I; and
(f) optionally converting Losartan of formula I to its potassium salt of the formula (F) by
treAT1ng with potassium hydroxide.

According to another embodiment, the present invention provides novel intermediate potassium salt 2-n-butyl-4-chloro-5-formyl imidazole (BCFI) of formula IV characterized by 1H NMR, 13C NMR and IR spectroscopy analysis.

According to yet another embodiment, the potassium salt 2-n-butyl-4-chloro-5-formyl imidazole (BCFI) of formula IV is isolated as solid.
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

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 cm"1.
According to one of the aspect of the present invention, Losartan Potassium Form-I is 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 0.5%.
According to further aspect of the present invention, Losartan Potassium Form-I prepared according to the process for the present invention is having mean particle size less than 400 mm, preferably less than 200 mm and more preferably less than 100 mm when measured with Malvern light scattering instruments.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS:
Figure-1 is an FTIR spectra of Losartan potassium Form -1 from 4000 cm-1 to 600 cm"1. Figure-2 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 radiAT1on source. DESCRIPTION OF THE INVENTION
The term "substantially free from regioisomer" means, losartan or its potassium salt prepared by the process for the present invention having regioisomer less than about 0.5% by area percentage of HPLC, preferably less than about 0.25%, more preferably less than about 0.1%, preferably less than about 0.07% by area percentage of HPLC.
According to first embodiment of the present invention, there is provided an improved process for the preparAT1on of losartan of formula (I) or its pharmaceutically acceptable potassium salt thereof substantially free from regioisomer of formula (la),

comprises of:
(a) reacting 2-n-butyl-4-chloro-5-formyl imidazole (BCFI) of formula III with potassium
hydroxide in suitable organic solvent to give potassium salt 2-n-butyl-4-chloro-5-formyl imidazole (BCFI) of formula IV;

CHO
CHO
(III)

(IV)

(b) reacting potassium salt 2-n-butyl-4-chloro-5-formyl imidazole (BCFI) of formula IV with 4'-bromomethyl-2-cyanobiphenyl (bromo OTBN) of formula V in polar organic solvent in absence of a base and a phase transfer catalyst to give cyano aldehyde of formula VI;
.CI

(c) reducing the cyano aldehyde of formula VI with reducing agent to give cyano alcohol of formula II;
.CI

(d) treAT1ng the cyano alcohol of formula III with inorganic azide and amine or salt thereof in a suitable organic solvent optionally in presence of phase transfer catalyst to form Losartan of formula I; and
N-NH
.CI
(e) optionally converting Losartan of formula I to its potassium salt of the formula (F) by treAT1ng with potassium hydroxide.

OH . .
N-N K+
.CI

According to one of the aspect of the invention, the 2-n-butyl-4-chloro-5-formyl imidazole (BCFI) of formula (III) is reacted with potassium hydroxide as in step (a) to obtain 2-n-butyl-4-chloro-5-formyl imidazole (BCFI) potassium salt of formula (IV) in a suitable organic solvent selected from 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, ethylbenzene and the like; nitrile solvents such as acetonitrile, propionitrile and the like; halogenated solvents such as dichloromethane, 1,2-dichloro methane, 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 aromAT1c hydrocarbons like toluene or xylene.
The reaction can be performed conveniently at room temperature till addition of potassium hydroxide thereby heAT1ng the reaction mixture to reflux temperature of solvent followed by azeotropic removal of water. The reaction mixture can be heated for 4-6 hours, thereby cooling to room temperature to afford potassium salt of 2-n-butyl-4-chloro-5-formyl imidazole (BCFI) of formula (IV). The compound of formula (IV) is isolated in solid form.
According to the further aspect of the present invention as in step (b), the potassium salt of 2-n-butyl-4-chloro-5-formyl imidazole (BCFI) of formula IV is reacted with 4'-bromomethyl-2-cyanobiphenyl (bromo OTBN) of formula V as in a polar organic solvent selected from C1-C4 alcohols like methanol, ethanol, isopropanol, n-propanol, n-butanol and the like; nitriles like acetonitrile, acrylonitrile and the like; ethers like diethyl ether, tetrahydrofuran, 1,4-dioxane and the like; amides like dimethylformamide, N-methyl acetamide and the like; dimethyl sulfoxide, N-methyl pyrrolidone and the like; preferably dimethylformamide.
Preferably, condensAT1on reaction of potassium salt of 2-n-butyl-4-chloro-5-formyl imidazole (BCFI) of formula IV with 4'-bromomethyl-2-cyanobiphenyl (bromo OTBN) of formula V in a polar organic solvent like dimethylformamide can be performed in absence of

a base or any phase transfer catalyst unlike the processes as reported in the prior art. The condensAT1on reaction can be performed below 25°C, preferably below 15°C and the reaction mixture was maintained for about 5-6 hours. The condensed product cyano aldehyde of formula (VI) is isolated by treatment with chilled water and stirring at room temperature.
According to another embodiment of the present invention, the condensAT1on of potassium salt of n-butyl-4-chloro-5-formyl imidazole (BCFI) of formula IV with 4'-bromomethyl-2-cyanobiphenyl (bromo OTBN) of formula V in dimethylformamide at lower temperature results in generAT1on of regioisomer of formula (Via) less than about 0.1% by area percentage of HPLC. Thus controlling formAT1on of regioisomer of formula (Via) will allow the formAT1on of losartan potassium substantially free from regioisomer of formula (la).

According to further aspect of the present invention as in step (c), the cyano aldehyde of formula (VI) can be reduced optionally in-situ with a suitable reducing agent selected from lithium aluminium hydride, sodium borohydride, potassium borohydride preferably sodium borohydride to obtain cyano alcohol of formula (II). The preferable addition of reducing agent can be in the range of about 20° to 45°C, preferably at about 25° to 30°C followed by heAT1ng to about 40° to about 45°C.
The suitable solvent for reduction can be selected from the group of C1-C4 alcohols like C1-C4 alcohols like methanol, ethanol, isopropanol, n-propanol, n-butanol, aromAT1c hydrocarbons like toluene, xylene, ethyl benzene and the like; preferably in toluene.
The cyano alcohol of formula (II) can be converted to losartan of formula (I) as in step (d) by treAT1ng it with an inorganic azide in a suitable organic solvent in presence of an amine or salt thereof. Examples of useful inorganic azide include azides of alkali metals or alkaline earth metals such as sodium, potassium, lithium, calcium, magnesium, etc. Azides of alkali metals are suitable and sodium azide is most suitable.
The amount of the inorganic azide used is 1 to 5 moles, preferably 1 to 3 moles, and calculated as hydrogen azide, per mole of a nitrile of cyano alcohol of formula (II). Desirably the inorganic azide is used in an equimolar amount relAT1ve to the amine or salt thereof.
Amine salts, which can be used in the invention, are formed from an amine and an
acid. Amine salts can be selected form pyridine hydrochloride, triethylamine hydrochloride,

piperidine acetate, methylamine hydrochloride, ethylamine hydrochloride, dimethylamine hydrochloride, diethylamine hydrochloride, dicyclohexylamine hydrochloride, morpholine hydrochloride, piperidine hydrobromide, triethylamine hydrobromide, tributylamine acetate, tributylamine hydrochloride, tertbutylamine hydrochloride and the like, preferably triethylamine hydrochloride.
Suitable organic solvents preferred in the reaction include but not limited to aromAT1c hydrocarbons inert to the reaction, for example, toluene, xylene, mesitylene, ethylbenzene, chlorobenzene, cumene, chlorotoluene etc. among which toluene and chlorobenzene are preferred, polar aprotic solvent such as DMF, N-methyl pyrrolidinone, Dimethyl imidazolidinone, dimethyl acetamide, preferably N-methyl pyrrolidinone and Dimethyl formamide and most preferably N-methyl pyrrolidinone.
The reaction temperature is selected from a wide range of 20 to 150°C, preferably between 80° to 120°C, most preferably between 90° to 110°C. The reaction time usually in the range of 20-40 hours, preferably 25-30 hours and most preferably between 28 to 30 hours. After the completion of the reaction the unreacted cyano alcohol of formula (II) remains in the organic solvent which can be easily recovered by distillAT1on and can be re-used.
The tetrazole formAT1on of cyano alcohol of formula (II) can also be performed optionally in presence of phase transfer catalyst selected from tetrabutyl ammonium bromide TBAB), benzyl triethyl ammonium chloride (TEBAC), polyethylene Glycol (PEG-200, 400, 600, 800, 1000 etc.,), preferably TBAB or PEG.
Losartan of formula (I) obtained from above process can be converted to its pharmaceutically acceptable potassium salt of formula (F) in C1-C4 alcoholic solvents like methanol, ethanol, isopropanol, n-propanol, n-butanol and the like; preferably methanol.
Product can be isolated by azeotropic distillAT1on of solvent and addition of an anti solvent. Anti-solvent is selected from n-hexane, n-heptane, acetone, ethyl acetate, acetonitrile, toluene and mixture tliereof, preferably acetone resulting in the formAT1on of the Losartan Potassium in polymorphic Form-I characterized by XRD, DSC and IR.
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" to 600 cm" having spectral absorbances: 764, 713, 886, 934, 953, 1358, 1340 cm"1.
According to another preferred embodiment, the present invention provides a process for the preparAT1on of losartan of formula (I) or its pharmaceutically acceptable potassium salt thereof substantially free from regioisomer of formula (la),


(I) ^ ^ (la)
comprises of:
(a) brominAT1ng OTBN of formula V with a suitable brominAT1ng agent to obtain bromo
OTBN of formula V;
Br H3C.
-CHO ^-^-/^M^^CHO
"K+
(III) (IV)
(b) reacting 2-n-butyl-4-chloro-5-formyl imidazole (BCFI) of formula III with potassium
hydroxide in suitable organic solvent to give potassium salt 2-n-butyl-4-chloro-5-formyl imidazole (BCFI) of formula IV;
(c) reacting potassium salt 2-n-butyl-4-chloro-5-formyl imidazole (BCFI) of formula IV of
step (b) with 4'-bromomethyl-2-cyanobiphenyl (bromo OTBN) of formula V of step (a)
in polar organic solvent in absence of a base and a phase transfer catalyst to give cyano
aldehyde of formula VI;

.CI
Br K'^

(d) reducing the cyano aldehyde of formula VI in-situ with reducing agent to give cyano alcohol of formula II;

(e) treAT1ng the cyano alcohol of formula II with inorganic azide and amine or salt thereof in a suitable organic solvent optionally in presence of phase transfer catalyst to form Losartan of formula I; and

(f) optionally converting Losartan of formula I to its potassium salt of the formula (V) by treAT1ng with potassium hydroxide.
According to another most preferred embodiment, the bromo OTBN of formula (V) can be prepared by brominAT1ng OTBN of formula (V) as in step (a) above before condensAT1on with potassium salt of 2-n-butyl-4-chloro-5-formyl imidazole (BCFI) of formula IV. The brominAT1on can be done by a suitable brominAT1ng agent selected from NBS, Br2, HBr, DBDMH (Dibromo dimethyl hydantoin) in presence of radical initiators like AIBN (Azobisisobutyronitrile), benzoyl peroxide etc., and preferably Dibromo dimethyl hydrantoin in presence of AIBN in non-polar solvent like methylene dichloride, ethyl acetate, toluene, xylene and the like preferably ethyl acetate at 40°-60°C.
According to another embodiment, the present invention provides novel intermediate potassium salt 2-n-butyl-4-chloro-5-formyl imidazole (BCFI) of formula IV characterized by 1H NMR, 13C NMR and IR spectroscopy analysis.

CHO

According to yet another embodiment, the potassium salt 2-n-butyl-4-chloro-5-formyl imidazole (BCFI) of formula IV is isolated as solid.
According to one of the aspect of the present invention, Losartan Potassium Form-I is 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 0.5%.
According to further aspect of the present invention, Losartan Potassium Form-I prepared according to the process for the present invention is having mean particle size less than 400 jxm, preferably less than 200 /mi and more preferably less than 100 /um when measured with Malvern light scattering instruments.
According to the most preferred embodiment of present invention, the process for the preparAT1on of Losartan Potassium of formula (F) can be illustrated by below mentioned schemes, which should not be considered as limiting the scope of the invention.



CHO
DMF

Scheme-8

Reduction

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 illustrAT1on only and should not be constructed as limit to the scope of the claims in any manner.
Examples:
Example-1: Potassium salt of 2-n-butyl-4-chloro-l//-imidazol-5-carboxaldehyde (BCFI)

100 g (0.5359 mole) 2-n-butyl-4-chloro-l//-imidazol-5-carboxaldehyde (BCFI) and 358 mL of toluene were taken into 1.0 liter 4-neck RBF equipped with Dean and stark. The reaction mixture was stirred for 10 minutes followed by the addition of potassium hydroxide solution (36 g KOH + 36 mL water) slowly at the room temperature. Then it was heated to get reflux temperature and with azeotropically distillAT1on for removal of water. The reflux temperature was maintained for 4 hours. The reaction mixture was cooled at the room temperature. The isolated product was filtered and washed with 36 mL of toluene to obtain 118 g (98%) potassium salt of 2-n-butyl-4-chloro-5-formyl imidazole (BCFI) of formula (IV).
Example-2: PreparAT1on of Bromo OTBN (V)


(V)

4'-methyl-biphenyl-2-carbonitrile of formula (V) 9.65 g (0.05 mole) and ethyl acetate 250 mL were taken into 500 mL 4-neck RBF. l,3-dibromo-5,5'-dimethylhydantoin (HBDMH) 1.79 g and the catalytic amount of radical initiators Azobisisobutyronitrile (A1BN) were added to the reaction mixture at room temperature. The reaction mixture was heated to 45°C for 3 hours. After the completion of the reaction the reaction mixture was treated with 100 mL (3%) Sodium bicarbonate solution. The separated organic layer was

treated with 5% brine solution. The organic layer was concentrated under reduced pressure. The residue was treated with isopropyl ether 25 mL to yield 5.4 g (95%) 4'-bromomethyl-bipheny 1 -2-carbonitri le.
Example-3: PreparAT1on of 4'-(2-Buryl-4-chloro-5-formyl-imidazol-l-yImethyl)-biphenyl-2-carbonitrile [Cyano aldehyde] (VI)

121g (0.445 mole) 4'-Bromomethyl-biphenyl-2-carbonitrile [Bromo OTBN] and 250 mL DMF were taken into RBF. The reaction mixture was stirred for 10 minutes cooled to 5°C to 10°C. lOOg (0.445 mole) potassium salt of 2-n-butyl-4-chloro-l//-imidazol-5-carboxaldehyde was added to the reaction mixture. The reaction mixture was maintained at about 5°C to 10°C for 5 hours and dumped into chilled water followed by constant stirring. The temperature was raised upto room temperature and stirred. The precipitated product was filtered and washed with water. The product was dried at 55°C to 60°C for 15 hours to obtain 160 g (95%) 4'-(2-Butyl-4-chloro-5-formyl-imidazol-l-ylmethyl)-biphenyl-2-carbonitrile (cyano aldehyde) of formula (VI).
Example-4: PreparAT1on of 4'-(2-Butyl-4-chloro-5-hydroxymethyl-imidazoI-l-yImethyI)-biphenyl-2-carbonitrile cyano alcohol (II)

100 g (0.2645 mole) (cyano aldehyde) i.e. 4'-(2-Butyl-4-chloro-5-formyl-imidazol-l-yl- methyl)-biphenyl-2-carbonitrile and 515 mL of toluene were taken into the RBF. The reaction mixture was stirred for 15 minutes at 25°C to 30°C. The solution of sodium borohydride (10.10 gm NaBFLj in 117.18 ml SDS) was slowly added to the reaction mixture and stirred for 15 minutes. The reaction mixture was heated at the temperature of about 40°C to 45°C followed by cooling to the room temperature. Toluene was distilled under vacuum.

The residue was further treated with toluene and stirred for 8 hours at the room temperature. Product was filtered and washed with 25 mL toluene to obtain 116 gm (95%) of 4'-(2-Butyl-4-chloro-5-hydroxymethyl-imidazol-l-ylmethyl)-biphenyl-2-carbonitrile (cyano alcohol) of formula (II)
Example-5: PreparAT1on of 2-butyI-4-chIoro-l- {[2'- (1H- tetrazoI-5-yI) [1, l'-biphenyl]-4-yl]-methyl}-l/f -imidazoIe-5-methanol (Losartan)

To a mixture of Triethyl amine hydrochloride (90g; 0.65 mole) in toluene (350 ml), Sodium azide (42g; 0.64 mole) was added. Reaction mass stirred for 1 hour and compound obtained in Examle-4 (50 g; 0.13 moles) and PEG-400 (12.5 mL) were added. Reaction mass was heated to 95-98°C and maintained for 34 hours. The progress of reaction was monitored by HPLC and after completion, reaction mass was cooled to 0-5° C and. methanol (250 mL) was added. The pH of reaction mass was adjusted to acidic by HC1 solution. After stirring for 20 minutes the pH of the reaction mass was again adjusted to 11 by KOH solution. Aqueous layer separated and washed with toluene. Ethyl acetate (450ml) was added to reaction mass and pH was adjusted to 4.5 and stirred overnight and obtained solid was filtered and dried. Example-6: PreparAT1on of 2-butyI-4-chIoro-l- {[2'- (1H- tetrazoI-5-yI) [1, l'-biphenyl]-4-yI]-methyl}-l/jT -imidazoIe-5-methanol (Losartan)

105g (0.276 mole) 2-n-butyl-4-chloro-l-[2'-cyanobiphenyl-4-yl)methyl]-5-(hydroxymethyl)- imidazole prepared by the process of Example-4 was taken in 210 ml of N-methyl pyrrolidinone at room temperature 25-30°C. The reaction mixture was treated with Triethyl amine hydrochloride 75g (0.545 mole) and sodium azide 35g (0.54 mole). The reaction temperature was raised to 100-105°C and maintained for 28-30 hours. The progress of the reaction was monitored by HPLC showed the absence of starting material. After the

completion of the reaction as monitored by HPLC, the reaction mixture was cooled to 45 -50°C and treated with 300 mL of toluene, 800 ml of water mixture under stirring. The organic layer was separated and aqueous layer was washed with 250 ml of toluene. The pH of aqueous layer was adjusted to 4.5 with acetic acid 70 mL and was stirred for 8 hours at 25-30°C. The aqueous solution was filtered and washed with water to get the Losartan (72%) of the formula (I). Melting point: 180.5 - 181.2.
Example-7: PreparAT1on of Potassium salt of 2-butyI-4-chIoro-l- {[2'- (1H- tetrazoI-5-yI) [1, l'-biphenyl]- 4-yI]-methyl}-l/f-imidazoIe-5-methanol (Losartan Potassium)

100 g (0.152 mol.) 2-butyI-4-chIoro-l-{[2'-(l//-tetrazoI-5-yI)-[l,l'-biphenyl]-4-yl]-methyl}-l// -imidazoIe-5-methanol (Losartan) was suspended in 250 mL methanol. The solution was heated to 45°C. A solution of 10 g (85%) potassium hydroxide (0.152 mol.) in water (6 mL) and methanol (50 mL) was added and the reaction mixture was heated to reflux under nitrogen atmosphere for nearly 6 hours. The reaction mass was cooled to 8-10°C and filtered and washed with 50 mL chilled methanol. The filtrate was treated with 1 g. charcoal and tittered through celite. Methanol solution was then concentrated at 45-50°C to remove most of methanol. 200 mL acetone was added and distillAT1on continued under reduced pressure to reduce the volume to approximately 120 mL. The white crystalline slurry was cooled to room temperature, filtered and product washed with 50 mL acetone and dried in vacuum oven to obtain Losartan Potassium. Yield: 60 g. (85%).
Advantages of the Invention:
1. The invention provides a process for preparAT1on of Losartan of formula (I) via an important intermediate i.e. potassium salt of 2-n-butyl-4-chloro-lH-imidazol-5-carboxaldehyde (BCF1) in isolated solid form.
2. The invention provides a process for the preparAT1on of cyano aldehyde by condensing potassium salt of BCFI and bromo OTBN in absence of a base and phase transfer catalyst.
3. The key starting materials like OTBN (4-methyl-biphenyl-2-carbonitrile) and BCFI (2-n-butyl-4-chloro-1H-imidazoI-5-carboxaldehyde) are easily available at low cost.
4. Cyano aldehyde of formula (VI) can be isolated or can be proceeded in-situ for the preparAT1on of cyano alcohol (II).
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5. The process for the preparAT1on of Losartan via potassium salt of BCFI avoids the formAT1on of regioisomer of formula (V) which in turns avoids the formAT1on of regioisomer impurity in Losartan Potassium less than about 0.1% by HPLC.
6. Losartan prepared by the above process is high purity > 99%.
7. The process is simple, cost effective, safe and commercially applicable for large scale productions.

ABSTRACT
The invention relates to an improved process for the preparAT1on of 2-butyl-4-chloro-l-[[(2'-(lH-tetrazole-5-yl)[1,1-biphenyl]-4-yl]methyl]-lH-imidazole-5-methanol or its pharmaceutically acceptable potassium salt, which comprises reacting bromo OTBN with BCFI or its salts in absence of a base and phase transfer catalyst to get a cyano aldehyde, the cyano aldehyde was reduced with sodium borohydride to give cyano alcohol followed by tetrazole formAT1on by reacting cyano alcohol with inorganic azide in presence amine or salt thereof to give 2-butyl-4-chloro-l-[[(2'-(lH-tetrazole-5-yl)[1,1'-biphenyl]-4-yl]methyl]-lH-imidazole-5-methanol and finally converting 2-butyl-4-chloro-l-[[(2'-(lH-tetrazole-5-yl)[1,1-biphenyl]-4-yl]methyl]-lH-imidazole-5-methanol to its pharmaceutically acceptable potassium salt by treAT1ng it with potassium hydroxide.