An Improved Process For Preparing Losartan Potassium

FORM 2 THE PATENTS ACT, 1970 (39 OF 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10; rule 13) 1. Title of the invention - AN IMPROVED PROCESS FOR PREPARING LOSARTAN POTASSIUM 2. Applicant(s) (a) NAME: ALEMBIC PHARMACEUTICALS LIMITED (b) NATIONALITY: An Indian Company. (c) ADDRESS: Alembic Campus, Alembic Road, Vadodara-390, 003, Gujarat, India 3. PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which is to be performed. :

Field of the invention: The present invention relates to an improved process for preparing Losartan Potassium of formula (I).

Background of the invention: The chemical name of Losartan is 2-Butyl-4-chloro-1-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methy]]-1H-imidazole-5-methanol and formula is C22H23CIN6O and molecular weight is 422.91. The drug is used in its potassium salt. The current pharmaceutical product containing this drug is being sold by Merck using the tradename Cozaar, in the form of tablets. Losartan is used as Antihypertensive. It is non-peptide angiotensin II receptor antagonist. It is used in the treatment of hypertension. It is also used in the treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria in patients with type 2 diabetes and a history of hypertension. It may be administered with other antihypertensive agents. US patent 5138069 describes a process for the preparation of Losartan Potassium which is shown in the scheme-I.

Scheme-I The process involves alkylating 4'bromomethyl-2-cyanobiphenyl with 2-n-butyl-4-chloro-5-(hydroxymethyl)imidazol in the presence of sodium methoxide and DMF to give 2-n-butyl-4-chloro-l-[2'-cyanobiphenyl-4-ylmethyl]-5-(hydroxymethyl)imidazol which is converted to losartan by reaction with sodium azide in the presence of sodium chloride and DMF. Losartan is converted to its potassium salt using 87% KOH solution.

Scheme-II WO2007020654 describes a process for the preparation of Losartan Potassium which is shown in the scheme-II.

The process involves alkylating 4'bromomethyl-2-cyanobiphenyl with 2-n-butyl-4-chloro-5-formyl imidazol in the presence of sodium hydroxide, DMF and phase transfer catalyst (PTC) to give 2-n-butyl-4-chloro-l-[2'-cyanobiphenyl-4-ylmethyl]-5-formylimidazol which is reduced with sodium borohydride to give 2-n-butyl-4-chloro-l-[2'-cyanobiphenyl-4-ylmethyl]-5-(hydroxymethyl)midazol which is further converted to losartan by reaction of sodium azide in the presence of triethylamine HC1 in polar solvent. Losartan is converted to its potassium salt using KOH solution. In the above processes, alkylation of 4'bromomethyl-2-cyanobiphenyl with 2-n-butyl-4-chloro-5-formyl imidazol in the solvent as mentioned hereinabove, gives an isomer which is reduced in next step to give isomeric alcohol along with the desired product. This unwanted isomeric alcohol is having the structural formula as shown below.

unwanted isomeric alcohol This impurity of unwanted isomeric alcohol is difficult to remove by conventional purification methods. Moreover the use of PTC makes the process economically unviable as it increases the raw material cost. It is therefore, there exists a need to develop an easy to operate, industrially feasible and yet cost effective process for preparing Losartan potassium. Further, this process should ensure the formation of isomeric impurity to a minimum desirable level. The present invention addresses these needs.

Present inventors have directed their research work towards developing a process for the preparation of Losartan Potassium which is devoid of the above disadvantages. The present inventors used DMF, aq. K2CO3 followed by reduction of insitu intermediate with NaBH4 & IPA. Serendipitously, it was observed that the use of 1-methylpyrrolidine instead of NMP (l-methy-2-pyrrolidinone) for the preparation of Losartan base produces the high yield & good purity of Losartan potassium. Moreover by the using 1-methylpyrrolidine the azide impurity formation is also minimized during the preparation of Losartan base. Object of the invention: The object of the present invention is to provide a process for the preparation of Losartan potassium comprising a step of treating the cyano alcohol compound of formula (I) with sodium azide in the presence of triethylamine hydrochloride (TEA-HC1) and 1-Methylpyrrolidine. The further object of the invention is to provide an improved process for preparation of Losartan Potassium comprising steps of: i) treating 4'-bromomethyl-2-cyanobiphenyl

with 2-buty]-4-chloro-5-formylirnidazole

in the presence of DMF and K2CO3 to give an insitu intermediate which is further reacted with sodium borohydride to give compound of formula

ii) reacting the cyano alcohol compound obtained in step (i) with sodium azide in the presence of triethylamine hydrochloride (TEA-HC1) and 1-Methylpyrrolidine to give losartan

iii) reacting Losartan with potassium hydroxide in methanol Another object of the present invention is to provide a process which gives Losartan Potassium with high purity. Another object of the present invention is to provide a process which is operationally simple and cost effective. Summary of the invention The present aspect of the invention is to provide a process for the preparation of Losartan potassium comprising a step of treating the cyano alcohol compound of formula (I) with

sodium azide in the presence of triethylamine hydrochloride (TEA-HCI) and 1-Methylpyrrolidine. In another aspect of the invention is to provide an improved process for preparation of Losartan Potassium comprising steps of: i) treating 4'-bromomethyl-2-cyanobiphenyl

with 2-butyl-4-chloro-5-formylimidazole

in the presence of DMF and K2CO3 to give an insitu intermediate which is further reacted with sodium borohydride to give compound of formula

ii) reacting the cyano alcohol compound obtained in step (i) with sodium azide in the presence of triethylamine hydrochloride (TEA-HC1) and 1-Methylpyrrolidine to give losartan

iii) reacting Losartan with potassium hydroxide in methanol Detailed description of the invention: The present embodiment of the invention is to provide a process for the preparation of Losartan potassium comprising a step of treating the cyano alcohol compound of formula (I) with sodium azide in the presence of triethylamine hydrochloride (TEA-HC1) and 1-Methylpyrrolidine. In another embodiment of the invention is to provide an improved process for preparation of Losartan Potassium comprising steps of:

with 2-butyl-4-chloro-5-formylimidazole

i) treating 4:-bromomethyl-2-cyanobiphenyI

in the presence of DMF and K2CO3 to give an insitu intermediate which is further reacted with sodium borohydride to give compound of formula

ii) reacting the cyano alcohol compound obtained in step (i) with sodium azide in the presence of triethylamine hydrochloride (TEA-HC1) and 1-Methylpyrrolidine to give losartan

iii) reacting Losartan with potassium hydroxide in methanol The synthetic reaction scheme of the present invention including the inventive step as shown in the scheme-I.

Scheme-I In the process of present invention, a mixture of 4'-Bromomethyl-2-cyanobiphenyl, DMF, base and 2-Butyl-4-chloro-5-formylimidazole is heated at 25°C to 40°C for about 2-5 hrs. The base is selected from K2C03, Na2C03, NaHC03, KHC03, NaOH, KOH, LiOH or mixtures thereof. The preferred base is anhydrous K2CO3. Sodium borohydride is charged to the reaction mixture at 30°C. Water and isopropanol are added to the wet cake and heated at about 75°C to about 85°C for 2 hours. The reaction mixture is cooled at room temperature and filtered. The solid is suck dried and dried in oven to give 2-n-Butyl-4-chloro-l-[2'-(cyanobiphenyl-4-yl)methyl]-5-(hydroxymethyl)-imidazole (I). A mixture of 2-n-Butyl-4-chloro-l-[2'-(cyanobiphenyl-4-yl) rnethyl]-5-(hydroxymethyl)-imidazole (I), sodium azide, triethylamine hydrochloride (TEA-HC1), 1-methylpyrrolidine and toluene are heated at 95-98°C. Caustic solution is added to it and the layers are separated. Acetone & activated charcoal is added for the decolourization.

Sulphuric acid is added to the aqueous layer and pH is adjusted to 4 to 5. The product is filtered and solid is washed with water. The obtained solid dry material is Losartan base. Potassium hydroxide solution is added to a mixture of Losartan base in methanol. The reaction mixture is heated to get clear solution. Acetone is added to it and stirred. The resulting precipitates are filtered, washed with acetone and suck dried. The solid is dried in oven to give Losartan potassium (II). The Losartan potassium obtained by above process is having polymorphic Form-I. Followings are the major advantage of the present invention: i) Yield improvement at the Tetrazole as well as Potassium stage formation of this invention. ii) Azide impurity gets controlled at the Tetrazole stage iii) Batch size increased at Tetrazole stage formation iv) Operates simply at Industrial scale & also makes process economically. The following examples illustrate the invention further. It should be understood, however, that the invention is not confined to the specific limitations set forth in the individual examples but rather to the scope of the appended claims. Example-1 Preparation of 4-{[2-butyl-4-chloro-5-(hydroxymethyl)-lH - imidazole-1-yl] methyl} biphenyl-2-carbonitrile A mixture of N, N-dimethyl formamide (300ml), anhydrous potassium carbonate (60.8 g), 2-Buthyl-4-chloro-5-formyl imidazole (72.0 g) & 4-bromomethyl-2-cyano biphenyl (100 g) charged into the RBF. The reaction mass was heated for 2-5 hrs at 25-40°C. Sodium borohydride (14.4 g) was charged to the reaction mixture at 30°C. The reaction mass was stirred & the reaction mixture was maintain for 2 hrs at 25-35°C. Water (900.0

ml) was added to it and isopropanol (350 ml) was added to the wet cake and heated at 75-80°C for 2 hours. The reaction mixture was cooled at room temperature and filtered with isopropanol. The solid was suck dried and dried in oven to give the title compound (100-120.0g). RESULTS: Wet weight : 120- 140 g Dry weight : 100-120 g Yield ratio (w/w) : 1.00-1.20 Theoretical yield (w/w) : 1.40 Example- 2 Preparation of 2-Butyl-4-chloro-l-[p-(o-lH-tetrazoI-5ylphenyl) benzyl] imidazole - 5-methanol A mixture of 2-n-Butyl-4-chloro-l-[2'-(cyanobiphenyl-4-yl)methyl]-5-(hydroxymethyl)-imidazole (100.0 g), sodium azide (48 g), triethyl amine hydrochloride (TEA-HC1) (100.0 g), 1-methylpyrrolidine (NMP) (75.0 ml) and toluene (100.0 ml) were heated at 95-98°C for 30-35 hours. The reaction mass was cooled upto 50-60°C. Caustic solution (16 g in 400ml water) was added to it and the layers were separated. The reaction mass was cooled upto 25-35°C. Charged Acetone (200 ml) into the reaction mass. Sulphuric acid was added to the aqueous layer and pH is adjusted to 4- to 5. The product was filtered and solid washed with water. The wet product is dried at 60-70° to obtain the Losartan base. RESULTS: Wet weight : 105- 130 g Dry weight : 90-105 g Yield ratio (w/w) : 0.90-1.05 Theoretical yield (w/w) : 1.11

Example- 3 Preparation of Losartan Potassium Potassium hydroxide (17.05 g) solution was added to a mixture of Losartan base (100.0 g) in methanol (170.0 ml). The reaction mixture was heated to get clear solution. Activated charcoal was added to the reaction mixture and stirred well. The mixture was filtered through hyflow bed to remove charcoal. The filtrate was distilled to evaporate the solvent completely. Acetone (300.0 ml) was added to it and stirred. The resulting precipitates were filtered and washed with acetone (50.0 ml) and suck dried. The solid was dried in oven to give Losartan potassium (87-95.0 g). RESULTS: Wet weight : 90-110g Dry weight : 87 - 95 g Yield ratio (w/w) : 0.87 - 0.95 Theoretical yield (w/w) : 1.07

We claim: 1. A process for preparation of Losartan Potassium

with2-butyl-4-chloro-5-formylimidazole

comprising steps of. (i) reacting 4' -bromomethy 1 -2-cyanobiphenyl in the presence of DMF and K2CO3 to give an intermediate which is further reacted with sodium borohydride to give compounq (I);

(ii) reacting the compound of formula (I) obtained in step (i) with sodium azide in the presence of triethylamine hydrochloride (TEA-HC1) and 1-methylpyrrolidine to give Iosartan;

(iii) reacting Losartan with potassium hydroxide in methanol to give Losartan potassium (II). 2. A process for preparation of Losartan Potassium (II) (i) reacting the compound of formula (I) with sodium azide in the presence of triethylamine hydrochloride (TEA-HC1) and 1-methylpyrrolidine to give losartan base;

(ii) conversion of losartan base to its potassium salt by any convention method.