FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10, rule 13]
AN IMPROVED PROCESS FOR THE PREPARATION OF
LOSARTAN
PIRAMAL ENTERPRISES LIMITED, a company incorporated under the Companies Act, 1956, of Piramal Tower, Ganpatrao Kadam Marg, Lower Parel, Mumbai - 400 013, State of 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 l-[l-[[2'-(2H-tetrazol-5-yl)biphenyl-4-yl]methyl]-2-butyl-4-chloro-lH-imidazoI-5-yl]methanol (Losartan represented as the compound of formula I). In particular, the present invention provides an improved process for the conversion of 4'-(2-butyI-4-chloro-5-hydroxymethyI-lH-imidazol-l-yl)-l,1'-biphenyI-2-carbonitrile (referred to herein as cyano losartan represented as the compound of formula II) to the compound of formula I (Losartan).
BACKGROUND OF THE INVENTION
Losartan, l-[l-[[2'-(2H-tetrazol-5-yl)biphenyl-4-yl]methyl]-2-butyl-4-chIoro-lH-imidazol-5-yl]methanol, is represented by the following formula I (hereinafter referred to as "the compound of formula [").

Losartan is an angiotensin II receptor antagonist agent mainly used to treat high blood pressure (hypertension). It is also used in the treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria in patients with type II diabetes and a history of hypertension. Losartan was the first angiotensin II

receptor antagonist to be marketed. The drug is used in its potassium salt form. Losartan potassium is marketed by Merck & Co. Inc. under the trade name Cozaar.
Several methods are reported in the art for the preparation of tetrazole compounds. Losartan, as is evident from its chemical structure, is also a tetrazole compound. Generally, preparation of terazole moiety involves the reaction of cyanide with trialkyltin azide.
The compound of formula I (Losartan) is disclosed in European Patent No. 0253310. This patent also described a process for the preparation of tetrazole moiety of the compound of formula I comprising cyclization of cyano group using sodium azide in the presence of N,N-dimethylformamide (DMF) as a solvent to obtain the reaction mixture. The resulting reaction mixture is then heated to 100°C for 2 days after which the temperature is raised to 120°C maintained for 6 days. The reaction mixture is then cooled to room temperature. To the reaction mixture again sodium azide is added and the resulting reaction mixture is heated to 120°C for 5 days. The reaction mixture is then filtered and the filtrate which is a solution is collected. The collected solution is then evaporated under vacuum to obtain the residue. To the residue, water and ethyl acetate are added and the two layers formed are separated. The ethyl acetate layer is then dried under vacuum to obtain yellow oil which after flash chromatography gives white crystalline solid of the compound of formula I. The process disclosed in said patent is carried over a very long period of 13 days. Also the yield of the compound of formula I obtained by the said process is moderate, which renders the process industrially not viable.
European patent no. 0578125 describes a process for the preparation of the compound of formula I which involves reaction of the compound of formula II with tri-n-octyltin azide in toluene as the solvent, and the resulting reaction mixture is heated at a temperature of 125°C for 31 hours. After completion of the reaction, the reaction mixture is cooled to room temperature. The reaction mixture is then

concentrated under reduced pressure. To the concentrated reaction mixture, ethanol and aqueous solution of sodium nitrite is added and pH of the reaction mixture is adjusted to 5 with concentrated hydrochloric acid. To the reaction mixture then ethyl acetate is added and again pH is adjusted to 1.1 with concentrated hydrochloric acid. The reaction mixture is diluted with n-hexane and pH of the reaction mixture is adjusted to 3.3 with aqueous sodium hydroxide to precipitate solid. The resulting precipitate is then filtered and washed with ethyl acetate-hexane mixture to obtain the compound of formula I. The resulting compound of formula I is then dried under vacuum. The said process of preparation of the compound of formula I involves use of tri-n-octyltin azide as one of the reagent for the reaction. Tin compounds such as tri-n-octyltin azide are environmentally hazardous chemicals and their disposals needs special method such as totally recovering metal from effluents, which needs ion exchange chromatography. Also the process disclosed in said patent requires long reaction time of 31 hours.
US patent no.7923566 describes a process for the preparation of the compound of formula I involving reaction of the compound of formula II with sodium azide in the presence of triethylamine hydrochloride in N-methylpyrrolidinone as the solvent at a temperature of 103-105°C for 28-30 hours. After completion of the reaction, the reaction mixture is cooled to 45-50°C. To the reaction mixture toluene and water are added. The two layers formed are separated and the aqueous layer is washed with toluene. The aqueous layer is then treated with activated carbon and filtered through celite. The pH of the aqueous layer is then adjusted to 4.3-4.5 with acetic acid to precipitate solid. The precipitated solid is then filtered and washed with water to obtain the compound of formula I. The process disclosed in said patent requires long reaction time of 28-30 hours. Also the yield of the compound of the formula I obtained by the said process is only 75%. Thus, the overall process is costlier and industrially not viable.

Based on the above discussion of the processes for the preparation of Losartan reported in the prior art, it can be said that the process for the preparation of Losartan (the compound of formula I) generally involves cyclization of the compound of formula II (cyano losartan) using trialkyltin azide or sodium azide. The main drawback of the processes hitherto reported in the prior art is the long duration of time required to carry out the reaction. Moreover, the prior art processes involved tedious workup procedures as well as separations by column chromatography requiring excessive production time, which in turn rendered the processes costlier and less eco-friendly and therefore, such processes are not viable for industrial manufacturing.
Hence, there is a need to develop a simple, commercially advantageous and industrially viable process for the preparation of Losartan, the compound of formula I which is carried over an overall reduced reaction time and provides the desired compound in good yield and of better purity.
The inventors of the present invention have now found that the compound of formula I can be obtained in good yield and better purity through an improved process.
OBJECT OF THE INVENTION
An object of the present invention is to provide an improved process for the preparation of the compound of formula I comprising reacting the compound of formula II with sodium azide, using a base catalyst.
Another object of the present invention is to provide an improved process for the preparation of the compound of formula I with 98% conversion of the compound of formula II to the desired compound of formula I.
Yet another object of the present invention is to provide an improved process for the preparation of the compound of formula I involving carrying out the reaction at

a shorter duration of time.
Further object of the present invention is to provide an improved process for the preparation of the compound of formula I, by avoiding any purification method for final product and providing the compound of formula I with yield of 91% and purity of > 99.0%.
SUMMARY OF THE INVENTION
In accordance with an aspect of the present invention, there is provided an improved process for the preparation of the compound of formula I comprising, reacting the compound of formula II with sodium azide in the presence of a base catalyst and triethylamine hydrochloride in an organic solvent.
The process for the preparation of the compound of formula I is depicted in scheme-l herein below:

Importantly, the process for the preparation of the compound of formula I of the present invention involving reaction of the compound of formula II with sodium azide using base catalyst results in 98% conversion of the compound of formula II to the desired compound of formula I with yield of 91% and purity of > 99.0%. Moreover, the reaction is carried over a shorter duration of time.

DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention relates to an improved process for the preparation of the compound of formula I.
According to the present invention, the improved process for the preparation of the compound of formula I involves use of a base catalyst.
Accordingly, there is provided a process for the preparation of the compound of formula I;

comprising,
reacting the compound of formula II,


with sodium azide in the presence of a base catalyst and triethylamine hydrochloride in an organic solvent to obtain a reaction mixture and isolating the compound of formula I from the resulting reaction mixture.
In accordance with an embodiment of the present invention, the base catalyst is selected from the group consisting of triazabicyclodecene (TBD), 1,4-diazabicyclo[2.2.2]octane (DBO), N,N-diisopropylethylamine (hunig's base), 1,1,3,3-tetramethylguanidine and trimethyl pyridine.
In accordance with an embodiment of the present invention, the base catalyst is used in an amount ranging from 0.1 to 0.5 equivalents based on the compound formula II.
In accordance with an embodiment of the present invention, the organic solvent is a polar aprotic solvent selected from N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide and dimethyl sulfoxide.
In an embodiment, the organic solvent is N-methyl-2-pyrrolidone.
In accordance with an embodiment of the present invention, the organic solvent is used in an amount ranging from 4 to 6 volumes based on the compound of formula II.

In accordance with an embodiment of the present invention, sodium azide is used in an amount ranging from 4 to 7 molar equivalents based on the compound of formula II.
In accordance with an embodiment of the present invention, triethyl amine hydrochloride is used in an amount ranging from 3 to 5 molar equivalents based on the compound of formula II.
In accordance with an embodiment of the present invention, the reaction of the compound of formula II with sodium azide in the presence of the base catalyst is carried out at a temperature ranging from 100°C to 120°C.
In accordance with an embodiment of the present invention, the reaction of the compound of formula II with sodium azide in the presence of the base catalyst is carried over a period of 11-18 hours.
The starting material of the process, i.e. the compound of formula II is a known compound which can be prepared by a person skilled in the art by following methods known in the art. For example, process described in US patent no.5138069 can be used for the preparation of the compound of formula II. The said compound of formula II can be prepared by the condensation of 2-n-butyl-4-chloro-5-(hydroxymethyl)imidazole with a 4-haIomethyl-2-cyanobiphenyl using sodium methoxide as a base and N,N-dimethylformamide (DMF) as a solvent to obtain the compound of the formula II.
In an embodiment of the present invention, the process for the preparation of the compound of formula I involves charging of the compound of formula II, sodium azide, triethylamine hydrochloride, base catalyst and an organic solvent to the reaction flask and the reaction mixture was heated to a temperature of 100-120°C for 11 to 18 hours. To the reaction mixture then toluene and water were charged at 50-60°C. The two layers formed were separated and the aqueous layer was treated with activated carbon at 50-60°C for 1 hour. The aqueous layer was then filtered

through celite and the solution was collected. To the solution, ethyl acetate was charged and the pH of the resulting reaction mass was adjusted 3.5-4 with aqueous acetic acid. The two layer formed were separated and ethyl acetate layer was distilled completely under vacuum to obtain residue. To the residue water was added and the reaction mass was stirred for 4-6 hours. The reaction mass was then filtered to obtain the compound of formula I as yellow crystalline solid.
The inventors of the present invention have observed that use of the base catalyst in the preparation of the compound of formula I promotes the reaction.
The base catalysts used in process of the present invention are amidine group compounds selected from the group consisting of triazabicyclodecene (TBD), 1,4-diazabicyclo[2.2.2]octane (DBO), N,N-diisopropylethylamine (hunig's base), 1,1,3,3-tetramethylguanidine and trimethyl pyridine. These amidine compounds form complexing ligand with reactant. Thus, in the process of preparation of the compound of formula I, the said bases act as a non-nucleophile organic base catalyst and in the presence of polar aprotic solvent give good results towards cyclization. Moreover, base catalysts provide an advantage in that they get easily washed out from the organic phase and do not interfere with the product, thereby providing the desired product i.e. the compound of formula I with good yield and purity of >99%, even without any additional step of purification.
The following examples which fully illustrate the practice of the preferred embodiments of the present invention are intended to be for illustrative purpose only and should not be construed in anyway to limit the scope of the present invention.
EXAMPLES: Example-1
Ina round bottom flask,the compound of formula II (50gm), sodium azide (50gm),

triethylamine hydrochloride (63gm) and l,4-diazabicyclo[2.2.2]octane (DBO)(3.7gm) in N-Methyl-2-pyrrolidone (40ml) were charged and the reaction mixture was gradually heated to 105-110°C for 12-15 hours. After completion of the reaction, toluene (150ml) and water (400ml) were added to the reaction mixture.The twolayers formed were separated and the aqueous layer wastreated with activated charcoal for 1 hr at 50-60°C. The aqueous layer was then filtered through celite and solution was collected. To the solution ethyl acetate (250ml) was added and the pH of the reaction mixture was adjusted to 3.5-4.0using aqueous acetic acid. The two layer formed were separated and ethyl acetate layer was distilled off completely under vacuum to obtain residue. To the residue water was added and the reaction mass was stirred form 4-6 hours to precipitate yellow crystalline solid. The precipitated solid was filtered to yield the compound of formula I. Yield 91%, HPLC purity 99%.
Melting point: 183.6 - 185.9°C
IR by KBR: 3373.21, 1579.2, 1468.54, 763.72, 556.34.
1H NMR: (DMSO-d6)
0.81(t,3H),1.21(sext,2H),1.43(quint,2H),2.49(t,2H),4.32(s,2H),5.23(s,2H),7.00-
7.66 (m,8H).
13C NMR: 8 values are
13.58,21.63,25.81,29.01,39.51,46.45,51.39,118.53,123.51,124.78,125.28,126.29,12
7.81,129.13,130.57,131.05,136.21,138.44,141.06,147.4,155.03.
Example-2
In a round bottom flask, the compound of formula II (50gm), sodium azide (50gm), triethylamine hydrochloride (63gm) and triazabicyclodecene (TBD)(4.6gm) in N-Methyl-2-pyrrolidone (40ml) were charged and the reaction mixture was gradually heated to 105-110°C for 12-15 hours. After completion of the reaction, toluene (150ml) and water (400ml) were added to the reaction mixture. The two layers

formed were separated. The aqueous layer was then treated with activated charcoal for 1 hr at 50-60°C. The aqueous layer was then filtered through celite and solution was collected. To the solution ethyl acetate (250ml) was added and the pH of the reaction mixture was adjusted to 3.5-4.0 using aqueous acetic acid. The two layer formed were separated and ethyl acetate layer was distilled off completely under vacuum to obtain residue. To the residue water was added and the reaction mixturewas stirred form 4-6 hours to precipitate yellow crystalline solid. The precipitated solid was filtered to yield the compound of formula I. Yield 91%, HPLC purity 99%.
Melting point: 183.6- 185.9°C
IR by KBR: 3373.21, 1579.2, 1468.54,763.72,556.34.
1H NMR: (DMSO-d6)
0.81(t,3H),1.21(sext,2H),1.43(quint,2H),2.49(t,2H),4.32(s,2H),5.23(s,2H),7.00-
7.66 (m,8H).
13C NMR: 5 values are
13.58,21.63,25.81,29.01,39.51,46.45,51.39,118.53,123.51,124.78,125.28,126.29,12
7.81,129.13,130.57,131.05,136.21,138.44,141.06,147.4,155.03.
Example-3
In a round bottom flask, the compound of formula II (50gm), sodium azide (50gm), triethylamine hydrochloride (63gm) and AyV-diisopropylethylamine(Hunig's base)(4.25gm) in N-Methyl-2-pyrrolidone (40ml) were charged and the reaction mixture was gradually heated to 105-110°C for 12-15 hours. After completion of the reaction, toluene (150ml) and water (400ml) were added to the reaction mixture. The two layers formed were separated. The aqueous layer was then treated with activated charcoal for 1 hr at 50-60°C. The aqueous layer was then filtered through celite and solution was collected. To the solution ethyl acetate (250ml) was added and the pH of the reaction mixture was adjusted to 3.5-4.0 using aqueous

acetic acid. The two layer formed were separated and ethyl acetate layer was distilled off completely under vacuum to obtain residue. To the residue water was added and the reaction mass was stirred form 4-6 hours to precipitate yellow crystalline solid. The precipitated solid was filtered to yield the compound of formula I. Yield 91%, HPLC purity 99%.
Melting point: 183.6- 185.9°C
IR by KBR: 3373.21, 1579.2, 1468.54, 763.72, 556.34.
1H NMR: (DMSO-d6)
0.8l(t,3H),1.21(sext,2H),1.43(quint,2H),2.49(t,2H),4.32(s,2H),5.23(s,2H),7.00-
7.66 (m,8H).
13C NMR: 5 values are
13.58,21.63,25.81,29.01,39.51,46.45,51.39,118.53,123.51,124.78,125.28,126.29,12
7.81,129.13,130.57,131.05,136.21,138.44,141.06,147.4,155.03.

WE CLAIM,
1. A process for the preparation of the compound of formula I,

comprising,
reacting the compound of formula II,

with sodium azide by using a base catalyst in the presence of triethylamine hydrochloride in an organic solvent at a temperature of 100-120°C for 11-18 hrs.

2. The process as claimed in claim 1, wherein base catalyst used is selected from the group consisting of triazabicyclodecene (TBD), 1,4-diazabicyclo[2.2.2]octane (DBO), N,N-diisopropylethylamine (hunig's base), 1,1,3,3-tetramethylguanidine and trimethyl pyridine.
3. The process as claimed in claim 1, wherein base catalyst is used in an amount ranging from 0.1 to 0.5 molar equivalents based on the compound formula II.
4. The process as claimed in claim 1, wherein the organic solvent is a polar aprotic solvent selected from N-methyl-2-pyrrolidone, dimethylformamide, dimethyl acetarnide and dimethyl sulfoxide.

5. The process as claimed in claim 1, wherein the organic solvent is N-methyl-2-pyrrolidone.
6. The process as claimed in claim 1, wherein the organic solvent is used in an amount ranging from 4 to 6 volumes based on the compound of formula II.
7. The process as claimed in claim 1, wherein said sodium azide is used in an amount ranging from 4 to 7 molar equivalents based on the compound of formula II.
8. The process as claimed in claim 1, wherein said triethylamine hydrochloride is used in an amount ranging from 3 to 5 molar equivalents based on the compound formula II.