DESC:RELATED PATENT APPLICATION(S)

This application claims the priority to and benefit of Indian Patent Application No. 202041003379 filed on January 24, 2020; the disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Losartan potassium.

BACKGROUND OF THE INVENTION

Losartan potassium is chemically known as 2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5-yl-phenyl) benzyl] imidazole-5-methanol monopotassium salt having the formula-I as mentioned below.

Formula-I

Losartan potassium is used for the treatment of antihypertension and marketed as Cozaar in USA. Losartan was first disclosed in the Patent US 5153197 and a process for the preparation of the same was disclosed as mentioned below.

The Patent US 7943647 assigned to Novartis discloses the preparation of losartan from 2-butyl-4-chloroimidazole-5-carboxaldehyde is mentioned below.

The Publication Journal of Medicinal Chemistry 1991, 34, pages 2525-2527 discloses the preparation of Losartan as mentioned below.

Although various routes exist for the preparation of Losartan potassium, most of the routes results in the API that have a risk of contamination with nitrosamines including NDEA (N-nitrosodiethylamine), NDMA (N-nitrosodimethylamine) and NMBA (N-Nitroso-N-methyl-4-aminobutyric acid) more than limit specified by the regulatory agencies. These nitrosamines are classified as probable human carcinogens. It is known that these impurities are formed during the introduction of tetrazole moiety in the APIs under certain conditions and when certain solvents, reagents and other raw materials are used.

Hence, there is a need for an improved process for the preparation of Losartan potassium that is economically significant and could reduce the amount of nitrosamine impurities in the API.

OBJECTS OF THE INVENTION

The primary object of the invention is to provide an efficient and industry feasible process for the preparation of Losartan potassium.

Another object of the invention is to provide an improved process for the preparation of highly pure Losartan potassium.

Yet another object of the invention is to provide an improved process for purification of losartan using solvent mixture of tetrahydrofuran and cyclohexane which is advantageous in achieving the final purity of Losartan potassium.

SUMMARY OF THE INVENTION

One aspect of the present invention is to provide a process for the preparation of Losartan potassium comprising the steps of:
(a) providing a mixture of losartan in tetrahydrofuran;
(b) optionally heating the mixture obtained in step (a);
(c) adding cyclohexane to the mixture obtained in step (a) or step (b);
(d) optionally cooling the mixture obtained in step (c);
(e) isolating the losartan from the mixture obtained in step (c) or (d); and
(f) preparing losartan potassium by treating the isolated losartan obtained in step (e) with a source of potassium.

Another aspect of the present invention is to provide a purification process for Losartan comprising the steps of:
(a) providing a mixture of losartan in tetrahydrofuran;
(b) optionally heating the mixture obtained in step (a);
(c) adding cyclohexane to the mixture obtained in step (a) or step (b);
(d) optionally cooling the mixture obtained in step (c); and
(e) isolating the losartan from the mixture obtained in step (c) or (d).

Yet another aspect of the present invention is to provide a purification process for Losartan comprising the steps of:
(i) providing a solution of losartan in water in the presence alkali;
(ii) adding triphenyl phosphine to solution obtained in step (i);
(iii) optionally stirring the obtained solution in step (ii);
(iv) filtering the contents obtained in step (ii) or step (iii);
(v) adjusting the pH of the filtrate obtained in step (iv) to 2 to 6;
(vi) optionally stirring the obtained solution obtained in step (v); and
(vii) isolating the resultant solid formed in step (v) or step (iv).

DETAILED DESCRIPTION OF THE INVENTION

The first embodiment of the present invention is to provide a process for the preparation of Losartan potassium comprising the steps of:
(a) providing a mixture of losartan in tetrahydrofuran;
(b) optionally heating the mixture obtained in step (a);
(c) adding cyclohexane to the mixture obtained in step (a) or step (b);
(d) optionally cooling the mixture obtained in step (c);
(e) isolating the losartan from the mixture obtained in step (c) or (d); and
(f) preparing losartan potassium by treating the isolated losartan obtained in step (e) with a source of potassium.
The step of providing a mixture of losartan in tetrahydrofuran as in step (a) according to the present invention may be obtained directly after the reaction or dissolving losartan formed in the reaction with tetrahydrofuran.

Preferably this step of providing a mixture of losartan in tetrahydrofuran is done by mixing losartan formed in the reaction with tetrahydrofuran.

The step of optionally heating the mixture obtained in step (a) as in step (b) according to the present invention may be done to obtain a solution of losartan in tetrahydrofuran or a suspension of losartan in tetrahydrofuran. The heating temperature is selected between 50°C to 70°C.

The step of optionally cooling the mixture obtained in step (c) as in step (d) according to the present invention may be done gradually cooling or immediately cooling to the required temperature. The required temperature for cooling is selected between 30°C to 0°C.

The step of isolating the losartan from the mixture obtained in step (c) or (d) as in step (e) according to the present invention may be done by filtering, centrifuging or any other means known in the state of art.

The step of preparing losartan potassium by treating the isolated losartan obtained in step (e) with a source of potassium as in step (f) according to the present invention wherein the source of potassium is methanolic potassium hydroxide solution.

Surprisingly the present inventors observed that the present process employing the solvent mixture of tetrahydrofuran and cyclohexane is advantageous than the other solvent mixtures used during the preparation of losartan in achieving the final purity of losartan potassium.

The second embodiment of the present invention is to provide a purification process for Losartan comprising the steps of:
(a) providing a mixture of losartan in tetrahydrofuran;
(b) optionally heating the mixture obtained in step (a);
(c) adding cyclohexane to the mixture obtained in step (a) or step (b);
(d) optionally cooling the mixture obtained in step (c); and
(e) isolating the losartan from the mixture obtained in step (c) or (d).

The step of providing a mixture of losartan in tetrahydrofuran as in step (a) according to the present invention may be obtained directly after the reaction or dissolving losartan formed in the reaction with tetrahydrofuran.

Preferably this step of providing a mixture of losartan in tetrahydrofuran is done by mixing losartan formed in the reaction with tetrahydrofuran.

The step of optionally heating the mixture obtained in step (a) as in step (b) according to the present invention may be done to obtain a solution of losartan in tetrahydrofuran or a suspension of losartan in tetrahydrofuran. The heating temperature is selected between 50°C to 70°C.

The step of optionally cooling the mixture obtained in step (c) as in step (d) according to the present invention may be done gradually cooling or immediately cooling to the required temperature. The required temperature for cooling is selected between 30°C to 0°C.

The step of isolating the losartan from the mixture obtained in step (e) according to the present invention may be done by filtering, centrifuging or any other means known in the state of art.

The third embodiment of the present invention is to provide a purification process for Losartan comprising the steps of:
(i) providing a solution of losartan in water in the presence alkali;
(ii) adding triphenyl phosphine to solution obtained in step (i);
(iii) optionally stirring the obtained solution in step (ii);
(iv) filtering the contents obtained in step (ii) or step (iii);
(v) adjusting the pH of the filtrate obtained in step (iv) to 2 to 6;
(vi) optionally stirring the obtained solution obtained in step (v); and
(vii) isolating the resultant solid formed in step (v) or step (iv).

The step of providing a solution of losartan in water as in step (i) according to the present invention may be prepared by dissolving losartan in water in the presence of alkali or is solution resulted in reaction in an alkaline medium.

The alkali employed in step (i) of the present invention is selected from the group comprising of carbonates and hydroxides of alkali and alkaline earth metal, preferably alkali hydroxides, most preferably sodium hydroxide.

The step of adjusting the pH of the filtrate obtained in step (iv) to 2 to 6 as in step (v) may be done by addition of acidic solution, more preferably dilute sulfuric acid.

The step of isolating the solid as in step (vii) according to the present invention may be done by filtering, centrifuging or any other means known in the state of art.

The preferred embodiment of the present invention is to provide a process for the preparation of Losartan potassium comprising the steps of:
(a) providing a mixture of losartan in tetrahydrofuran;
(b) heating the mixture obtained in step (a);
(c) adding cyclohexane to the mixture obtained in step (b);
(d) cooling the mixture obtained in step (c);
(e) isolating the losartan from the mixture obtained in step (d); and
(f) preparing losartan potassium by treating the isolated losartan obtained in step (e) with a source of potassium.

The present invention is explained in detail with reference to the following examples described below, which are given for the purpose of illustration only and are not intended to limit the scope of the invention.

EXAMPLES

Example-1: Preparation of 2-n-Butyl-4-chloro-5-(hydroxymethyl)-1-[[2’-(cyano)-[1,1’-biphen-4-yl]-methyl]-1H-imidazole
To a mixture of potassium carbonate (121.5 gm), dimethylformamide (600 ml), 2-butyl-4-chloro-5-formyl-imidazole (144.0 gm), 4’-Bromomethyl-2-cyano-biphenyl (200 gm) was added at 5°C and stirred for 2 hours at 5°C. The progress of the reaction was monitored by HPLC. After completion of the reaction, sodium borohydride (28.90 gm) was added to the reaction mass at 20°C. The reaction mixture was heated to 30°C and stirred for 2 hours at same temperature. The progress of the reaction was monitored by HPLC. After completion of the reaction, water (1800 ml) was added to the reaction mass at 40°C followed by isopropyl alcohol (700 ml) at 40°C and stirred for 1 hour at the same temperature. The stirred reaction mass was heated to 80°C and stirred for 3 hours at the same temperature. Then the reaction mass was cooled to 30°C and stirred for 2 hours at the same temperature. The resultant solid was filtered, washed with water (1800 ml). The wet solid was heated with toluene (1000 ml) to 108°C and stirred for 1 hour at 108°C. The heated contents were then cooled to 30°C and stirred for 2 hours at same temperature. The resultant solid was filtered, washed with toluene (200 ml) and dried under vacuum. Yield: 85.0%; Purity: 99.8% by HPLC

Example-2: Preparation of Losartan
Step-A: To a mixture of 2-n-butyl-4-chloro-5-(hydroxymethyl)-1-[[2’-(cyano)-[1,1’-biphen-4-yl]-methyl]-1H-imidazole (500 gm), toluene (750 ml) and triethylamine hydrochloride (500 gm); sodium azide (240 gm) was added at 30°C followed by N-methyl-2-pyrrolidone (250 ml) and then heated to 98°C. The reaction mixture was stirred for 40 hours at the same temperature. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was cooled to 65°C.

Step-B: To the cooled reaction mass obtained in step-A, sodium hydroxide solution (275 gm of sodium hydroxide in 1850 ml of water) was added at 65°C and stirred for 1 hour at the same temperature. The reaction mass was allowed to settle to form a triphasic layer at 65°C. The middle layer was separated at 65°C. To the separated middle layer, water (1500 ml) was added at 65°C followed by the addition of toluene (500 ml) at 65°C and stirred for 30 minutes at the same temperature. The reaction mass was allowed to settle to form a biphasic layer. The bottom aqueous layer was separated at 65°C. To the separated aqueous layer, sodium metabisulfite (37.5 gm) was added at 65°C followed by toluene (500 ml) at 65°C and stirred for 30 minutes at 65°C. The reaction mass was allowed to settle to form a biphasic layer at 65°C. The bottom aqueous layer was separated at 65°C.

Step-C: To the separated bottom aqueous layer obtained in step-B, water (1500 ml) was added at 65°C and then cooled to 30°C. To the cooled reaction mass, triphenylphosphine (6.50 gm) was added at 30°C and stirred for 2 hours at the same temperature. To the stirred reaction mass, activated carbon (10 gm) was added at 30°C; stirred for 30 minutes at 30°C and then filtered through hyflo bed. The filtrate was cooled to 20°C. To the cooled filtrate, ethyl acetate (400 ml) was added at 20°C and the pH of the reaction mass was adjusted to 4.0 by dilute sulfuric acid at 20°C for 2 hours and stirred for 3 hours at 20°C. The resultant solid was filtered and washed with water (500 ml) at 30°C. Yield: 588 gm of wet solid

Step-D: To the wet solid obtained in step-C (235 gm) was heated with methanol (225 ml) to 50°C and stirred for 1 hour at 50°C. The heated contents were then cooled to 30°C and stirred for 2 hours at 30°C. The cooled contents at 30°C was further cooled to 5°C and stirred for 2 hours at 5°C. The resultant solid was filtered, washed with chilled methanol (90 ml) and dried. %Yield: 85%; Purity: 99.4% by HPLC

Example-3: Preparation of Losartan
Step-A: To a mixture of 2-n-butyl-4-chloro-5-(hydroxymethyl)-1-[[2’-(cyano)-[1,1’-biphen-4-yl]-methyl]-1H-imidazole (250 gm), toluene (375 ml) and triethylamine hydrochloride (250 gm); sodium azide (119.8 gm) was added at 30°C followed by N-methyl-2-pyrrolidone (125 ml) and then heated to 98°C. The reaction mixture was stirred for 36 hours at the same temperature. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was cooled to 65°C.

Step-B: To the cooled reaction mass obtained in step-A, sodium hydroxide solution (137.5 gm of sodium hydroxide in 925 ml of water) was added at 65°C and stirred for 1 hour at the same temperature. The reaction mass was allowed to settle to form a triphasic layer at 65°C. The middle layer was separated at 65°C. To the separated middle layer, water (750 ml) was added at 65°C followed by the addition of toluene (250 ml) at 65°C and stirred for 45 minutes at the same temperature. The reaction mass was allowed to settle to form a biphasic layer. The bottom aqueous layer was separated at 65°C. To the separated aqueous layer, sodium metabisulfite (18.8 gm) was added at 65°C followed by toluene (250 ml) at 65°C and stirred for 30 minutes at 65°C. The reaction mass was allowed to settle to form a biphasic layer at 65°C. The bottom aqueous layer was separated at 65°C.

Step-C: To the separated bottom aqueous layer obtained in step-B, water (750 ml) was added at 65°C and then cooled to 30°C. To the cooled reaction mass, triphenylphosphine (3.3 gm) was added at 30°C and stirred for 2 hours at the same temperature. To the stirred reaction mass, activated carbon (12.5 gm) was added at 30°C; stirred for 30 minutes at 30°C and then filtered through hyflo bed at 30°C. The filtrate was cooled to 20°C. To the cooled filtrate, ethyl acetate (400 ml) was added at 20°C and the pH of the reaction mass was adjusted to 6.5 by dilute sulfuric acid at 20°C. To the pH adjusted reaction mass, losartan crystals (500 mg) were seeded, then the pH was adjusted to 3.5 to 4.5 at 20°C and stirred for 3 hours at 20°C. The resultant solid was filtered and washed with water (500 ml) at 30°C.

Step-D: The wet solid obtained in step-C was added to the water (2250 ml) followed by the addition of sodium hydroxide solution (26.3 gm of Sodium hydroxide in 250 ml of water) and stirred for 30 minutes at 30°C to obtain a solution. Methylene chloride (750 ml) was added to the obtained solution and stirred for 20 minutes at 30°C. The mixture was allowed to settle to form a biphasic layer at 30°C. The top aqueous layer was separated and cooled to 20°C, then the pH was adjusted to 6 to 7 by the addition of dilute sulfuric acid. Ethyl acetate (200 ml) was added to the pH adjusted solution followed by the addition of losartan crystals (500 mg) and stirred for 1 hour at 20°C. The pH of the solution was again adjusted to 3.5 to 4.5 by the addition of dilute sulfuric acid and then stirred for 2 hours at 20°C. The resultant solid was filtered, dried and washed with water (250 ml).

Step-E: The wet solid obtained in step-D was added to methanol (312.5 ml) and heated to 50°C and stirred for 1 hour at 50°C. The heated contents were then cooled to 30°C and stirred for 2 hours at 30°C. The contents stirred at 30°C was further cooled to 5°C and stirred for 2 hours at 5°C. The resultant solid was filtered, washed with chilled methanol (125 ml) and dried. Yield: 230 gm; Purity: 99.3% by HPLC.

Example-4: Purification of Losartan
A mixture of crude losartan (220 gm) and tetrahydrofuran (1200 ml) is heated to 65°C and stirred for 30 minutes at the same temperature. To the heated contents, cyclohexane (1200 ml) was added and stirred for one hour at 65°C. The stirred reaction mass was cooled to 15°C and stirred for 2 hours. The resultant solid was filtered, washed with cyclohexane (100 ml) and dried. Yield: 85%

Example-5: Preparation of Losartan potassium
To a mixture of losartan (40 gm) and methanol (200 ml), methanolic potassium hydroxide solution (6.5 gm of potassium hydroxide in 40 ml of methanol) was added and stirred for 1 hour at 30°C. Activated carbon (4 gm) was added to the reaction mass and stirred for 30 minutes at 30°C. The stirred reaction mass was filtered through hyflo bed. The filtrate was concentrated at 55°C under vacuum. The concentrated residue was heated to 55°C after addition of methyl ethyl ketone (116 ml) and methanol (4 ml) and stirred for 1 hour at 50 to 55°C. The heated contents were cooled to 30°C and stirred for 2 hours at 30°C. The cooled contents at 30°C was further cooled to 5°C and stirred for 2 hours at 5°C. The resultant solid was filtered under nitrogen atmosphere, washed with chilled methyl ethyl ketone (20 ml) and dried under vacuum. Yield: 85%

Example-6: Preparation of Losartan potassium
To a mixture of losartan (60 gm) and methanol (300 ml), methanolic potassium hydroxide solution (6.5 gm of potassium hydroxide in 40 ml of methanol) was added and stirred for 1 hour at 30°C. Activated carbon (6 gm) was added to the reaction mass and stirred for 30 minutes at 30°C. The stirred reaction mass was filtered through hyflo bed. The filtrate was concentrated at 55°C under vacuum. The concentrated residue was heated to 55°C after addition of acetone (232 ml) and methanol (7 ml) and stirred for 1 hour at 50 to 55°C. The heated contents were cooled to 30°C and stirred for 2 hours at 30°C. The cooled contents at 30°C was further cooled to 5°C and stirred for 2 hours at 5°C. The resultant solid was filtered under nitrogen atmosphere, washed with chilled acetone (20 ml) and dried under vacuum. Yield: 85%
,CLAIMS:
1. A process for the preparation of Losartan potassium comprising the steps of:
(a) providing a mixture of losartan in tetrahydrofuran;
(b) optionally heating the mixture obtained in step (a);
(c) adding cyclohexane to the mixture obtained in step (a) or step (b);
(d) optionally cooling the mixture obtained in step (c);
(e) isolating the losartan from the mixture obtained in step (c) or (d); and
(f) preparing losartan potassium by treating the isolated losartan obtained in step (e) with a source of potassium.

2. The process as claimed in claim 1, wherein the source of potassium employed in step (f) is methanolic potassium hydroxide solution.

3. A purification process for Losartan comprising the steps of:
(a) providing a mixture of losartan in tetrahydrofuran;
(b) optionally heating the mixture obtained in step (a);
(c) adding cyclohexane to the mixture obtained in step (a) or step (b);
(d) optionally cooling the mixture obtained in step (c); and
(e) isolating the losartan from the mixture obtained in step (c) or (d).

4. The process as claimed in claim 1 or 3, wherein in step (b) heating is done to obtain a solution of losartan in tetrahydrofuran or a suspension of losartan in tetrahydrofuran, and
wherein the heating temperature is selected between 50°C to 70°C.

5. The process as claimed in claim 1 or 3, wherein the cooling in step (d) is done by gradually or immediately cooling to the required temperature, and
wherein the required temperature for cooling is selected between 30°C to 0°C.

6. A purification process for Losartan comprising the steps of:
(i) providing a solution of losartan in water in the presence alkali;
(ii) adding triphenyl phosphine to solution obtained in step (i);
(iii) optionally stirring the obtained solution in step (ii);
(iv) filtering the contents obtained in step (ii) or step (iii);
(v) adjusting the pH of the filtrate obtained in step (iv) to 2 to 6;
(vi) optionally stirring the obtained solution obtained in step (v); and
(vii) isolating the resultant solid formed in step (v) or step (iv).

7. The process as claimed in claim 6, wherein the alkali employed in step (i) is selected from the group comprising of carbonates and hydroxides of alkali and alkaline earth metal.

8. The process as claimed in claim 7, wherein alkali is sodium hydroxide.

9. The process as claimed in claim 6, wherein in step (v) the pH is adjusted by addition of acidic solution, and wherein the acidic solution is dilute sulfuric acid.

10. The process as claimed in claims 1-9, wherein the step of isolating the losartan is done by filtering or centrifuging.