Claims:
1) A process for preparation of Losartan potassium having the Losartan Azido impurity within the threshold of toxicological concern (TTC) which comprises;
a) Reacting 4'-{{2-butyl-4-chloro- 5-{hydroxymethyl)-1 H imidazol-1-yl]methyI}biphenyI-2- carbonitrile of formula-II with sodium azide in a solvent selected from the group consisting of aromatic hydrocarbon solvent, ethers, amides or mixtures thereof to obtain Losartan base;
b) treating Losartan base with an agent selected from the group consisting of Zinc, Sodium sulfide, Hydrose and NaNO2, to obtain crude Losartan base; and
c) reacting the crude Losartan base with potassium hydroxide to obtain Losartan potassium.

2) The process as claimed in claim 1, wherein the aromatic hydrocarbon solvent is selected from the group consisting of benzene, toluene and xylene.
3) The process as claimed in claim 1, wherein the agent is NaNO2.
4) The process as claimed in claim 1, wherein the step 1b is conducted at ambient temperature or at elevated temperatures.
5) The process as claimed in claim 1, wherein the reaction of step 1a is conducted in presence of tri ethylamine HCl salt or tributyl ammonium bromide salt.
6) The process as claimed in claim 1, wherein the agent is added into reaction mixture obtained after completion of step 1a reaction.
7) The process as claimed in claim 1, wherein the reaction of step 1c is conducted in alcohol solvents.
8) The process as claimed in claim 7, wherein the alcohol solvent is selected from the group consisting of methanol, ethanol, n-propanol, i-propanol and butanol.
9) The process as claimed in any one of the preceding claims, wherein, the Losartan base obtained having the Losartan Azido impurity within the threshold of toxicological concern (TTC).
, Description:Field of the invention:
This invention relates to improvement in process for preparation of Losartan Potassium. More specifically, this invention relates to a commercial process for preparation of high purity Losartan potassium having azido impurity within the TTC limits.

Background of Invention:
Among cardiovascular drugs, Angiotensin II receptor antagonists like losartan potassium are prominently used as an active ingredient in the management of hypertension. Losartan potassium plays an effective role in patients having difficulty in tolerating ACE inhibitors. The chemical name of Losartan potassium is 2-n-Butyl-4-Chloro-1[((2'-tetrazol-5-yl)-1,1'-biphenyl-4-yl)methyl]-imidazole-5-methanol potassium.

Losartan potassium was first reported in US5138069. It is known in the art that Losartan potassium is synthesized by reacting Losartan base with KOH. The Losartan base in turn is known to be synthesized by detritylation of 2-n-butyl-4-chloro-5-hydroxymethyl-1-[((2'-triphenylmethyltetrazole-5-yl)biphenyl-4-yl)methyl]imidazole (compound of formula (I)) as mentioned below.

The synthesis of Trityl Losartan (of form (I) is known in the art, for example, 34 J. MED. CHEM. 2525-27 (1991); 59 J. ORG. CHEM. 6391-94 (1994) and U.S. Pat. No. 5,138,069. Trityl Losartan and Losartan acid may alternatively be prepared using the reactions and techniques described in US 5,138,069 and WO93/10106.

The preparation of Losartan base from Trityl Losartan (the compound of formula (I)) by acid-catalyzed cleavage of the trityl group is disclosed in U.S. Pat. No. 5,281,603. Another method disclosed to prepare Losartan base from trityl losartan is disclosed in U.S. Pat. No. 5,281,604; in this process, Trityl Losartan (III) is refluxed in a mixture of methanol and tetrahydrofuran for 18 hours to get Losartan base.

Another route of preparation has been reported in various patents/patent publications, viz., US5629331, , CN112679476 & CN110467604 in which 4'-{{2-butyl-4-chloro- 5-{hydroxymethyl)-1 H imidazol-1-yl]methyI}biphenyI-2- carbonitrile of formula-II is reacted with sodium azide in aromatic hydrocarbon solvent such as toluene in presence of Triethyl amine hydrochloride for about 35 hours. After completion of reaction, the reaction mass was treated with NaOH solution followed by separation of layers. Then pH of the reaction mixture adjusted with dilute HCl to about 4 and filtered to obtain Losartan base.

The Losartan base may be converted into its potassium salt by reacting with KOH in presence of alcohols such as methanol and ethanol.
European Directorate for the Quality of Medicines & HealthCare (EDQM) recently (April 2021) reported that it had received information about the presence of azido impurity in Losartan potassium active substance. The impurity called, 5-[4'-[(5-(azidomethyl)-2-butyl-4-chloro-1H-imidazol-1-yl)methyl]-[1,1'-biphenyl]2-yl]-1H-tetrazole (CAS 727718-93-6) (“Losartan azido impurity”) is having following structure.

Losartan azido impurity is found to be mutagenic. Therefore, the holders of a Certificate of Suitability (CEP) were requested to take corrective action to ensure that such impurities do not exceed their acceptable limits.

Objective of Invention
Therefore, the objective of the present invention is to provide industrially feasible process to prepare high purity Losartan potassium having the Losartan Azido impurity within the threshold of toxicological concern (TTC).

Summary of Invention
In pursuit of the above objective, the present inventors have, surprisingly, found a novel process to prepare high purity Losartan potassium. Accordingly, the present invention provides a process for preparation of Losartan potassium having the Losartan Azido impurity within the threshold of toxicological concern (TTC) limits, which comprises;
a) Reacting 4'-{{2-butyl-4-chloro- 5-{hydroxymethyl)-1 H imidazol-1-yl]methyI}biphenyI-2- carbonitrile of formula-II with sodium azide in a solvent selected from aromatic hydrocarbon solvent, ethers, amides or mixtures thereof to obtain Losartan base; and
b) treating Losartan base with an agent selected from Zinc in basic medium, Sodium sulfide, Hydrose and NaNO2 to obtain crude Losartan base; and
c) reacting the crude Losartan base with potassium hydroxide to obtain Losartan potassium.

In a preferred embodiment, the present invention provides a process for preparation of Losartan potassium having the Losartan Azido impurity within the threshold of toxicological concern (TTC) limits which comprises;
a) Reacting 4'-{{2-butyl-4-chloro- 5-{hydroxymethyl)-1 H imidazol-1-yl]methyI}biphenyI-2- carbonitrile of formula-II with sodium azide in a solvent selected from aromatic hydrocarbon solvent, ethers, amides or mixtures thereof to obtain Losartan base in reaction mixture;
b) treating Losartan base in reaction mixture with an agent selected from Zinc in basic medium, Sodium sulfide, Hydrose and NaNO2 to obtain crude Losartan base; and
c) reacting the crude Losartan base with potassium hydroxide in alcohol solvent to obtain Losartan potassium.

Detailed description of the invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. To describe the invention, certain terms are defined herein specifically as follows.

Unless stated to the contrary, any of the words, “including”, “includes”, “comprising”, and “comprises” mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items.

The present inventors have, surprisingly, found a novel process to prepare high purity Losartan potassium. Accordingly, the present invention provides a process for preparation of Losartan potassium which comprises;
a) Reacting 4'-{{2-butyl-4-chloro- 5-{hydroxymethyl)-1 H imidazol-1-yl]methyI}biphenyI-2- carbonitrile of formula-II with sodium azide in a solvent selected from aromatic hydrocarbon solvent, ethers, amides or mixtures thereof to obtain Losartan base;
b) treating Losartan base with an agent selected from Zinc in basic medium, Sodium sulfide, Hydrose and NaNO2 to obtain crude Losartan base; and
c) reacting the crude Losartan base with potassium hydroxide to obtain Losartan potassium.

In a preferred embodiment, the reaction of 4'-{{2-butyl-4-chloro- 5-{hydroxymethyl)-1 H imidazol-1-yl]methyI}biphenyI-2- carbonitrile of formula-II with sodium azide is conducted in presence of tri ethylamine HCl salt or tributyl ammonium bromide salt.

The reaction may be conducted in suitable solvents such as aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane, tetrahydrofuran and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone and the like.

Typically the reaction is conducted is conducted at ambient temperature or at elevated temperatures, for 20-35 hours for completion of reaction. After completion of reaction, added an agent selected from Zinc in basic medium, Sodium sulfide, Hydrose and NaNO2 for degrading azide impurity formed during the synthesis of Losartan base.

In a preferred embodiment, the agent is added to the reaction mixture obtained after completion of reaction. The agents include Zinc in basic medium, Sodium sulfide, Hydrose and NaNO2. After completion of treatment with the agent, pH of the reaction mixture is adjusted to 3.3-4.3 using dil. HCl followed by isolation of crude Losartan base by conventional methods such as filtration.

Crude Losartan base is further converted to Losartan potassium by reacting with potassium hydroxide in presence of an alcoholic solvent, which include methanol, ethanol, n-propanol, i-propanol and the like.

The following examples, which include preferred embodiments, intended to illustrate the practice of this invention. It is being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

EXAMPLES:

Example-1: Synthesis of 4'-{{2-butyl-4-chloro- 5-{hydroxymethyl)-1 H imidazol-1-yl]methyI}biphenyI-2- carbonitrile of formula-II.
Into a 1000 ml flask equipped with a reflux condenser, thermometer and stirrer were placed 141.5 ml Methylene dichloride (MDC), 32.5 g ( 0.168 moles) Ortho Tolyl Benzo Nitrile (OTBN), 0.23 gm Azo bis isobutyl iso Nitrile (AIBN), 1.53 gm of DDH. The mixture was heated to reflux. Added second lot of DDH solution prepared by mixing 3.825 DDH in 5.8 ml MDC and refluxed for another hour. Added third lot of DDH solution prepared by mixing 3.825 DDH in 5.8 ml MDC and refluxed for another hour. Added fourth lot of DDH solution prepared by mixing 3.06 DDH in 4.5 ml MDC and reflux continued till the completion of reaction. After completion of reaction, the reaction mixture was cooled to room temperature and water was added. Separated organic layers, added sodium bicarbonate solution in MDC layer. Stirred and separated organic layer. MDC distilled under vacuum. Added water and distilled azeotropically to remove MDC completely. Added toluene followed by sodium hydroxide solution. Charged 26.32 g (0.141 moles) 2- Butyl -4-Chloro-5-Formyl Imidazole (BCFI) followed by 3.2 g (0.010 moles) Tetra butyl ammonium bromide. Stirred the reaction mass till the completion of reaction. After completion of reaction, separated aqueous layer. Organic layer washed with sodium hydroxide solution. Organic layer washed with Sodium metabisulphite solution. Finally organic layer washed with water. Added 3.55 g (0.094 moles) Sodium borohydride followed by Methanol and stirred till the completion of reaction. After completion of reaction, the reaction mass was cooled to 100C. Added water into reaction mass and filtered and dried to obtain 47.2 g of compound of formula-II.
Purity (By HPLC): 99.0%

Example-2: Synthesis of Losartan base (Using Sodium nitrite)
Into a 1000 ml flask equipped with a reflux condenser, thermometer and stirrer were placed 100 ml Toluene, 100 g (0.26 moles) compound of formula-II, 117.6 g (0.855 moles) Tri ethylamine HCl and 55.2 g (0.85 moles) Sodium azide. Reaction mass was heated to reflux and maintained till completion of reaction. After completion of reaction, the reaction mass was cooled and added 100 ml toluene followed by Sodium hydroxide solution. Separated lower aqueous layer, added 400 ml water to upper layer and separated lower aqueous layer. Again added 56.7 ml water to upper layer and separated lower aqueous layer. Combined both the aqueous layer and distilled 100-110 ml water. Added same amount of fresh water (100-110 ml). Added 21.03 g (0.305 moles) Sodium nitrite solution and stirred for 1 hr at 65-750C. Reaction mass was cooled and adjusted pH 3.3-4.3 using dil. HCl . Filtered and washed with water. Added wet material in aqueous Sodium hydroxide solution followed by 18.13 g (0.263 moles) Sodium nitrite solution and heated to reflux till the completion of reaction. After completion of reaction, the reaction mass was cooled and added 1.14 g (0.0065 moles) Hydrose followed by Activated carbon. Filtered and adjusted the pH 3.3-4.3 using dil. HCl. Reaction mass was filtered and slurried in water. Wet solid refluxed in IPA at 80-820C for 1 hr. Reaction mass was cooled and filtered and dried to give 97±4 gm of Losartan base.
Purity (By HPLC): 99.0%
Losartan azide content (By HPLC): 3 ppm

Example-3: Synthesis of Losartan base (Using Hydrose)
Into a 1000 ml flask equipped with a reflux condenser, thermometer and stirrer were placed 100 ml Toluene, 100 g (0.26 moles) compound of formula-II, 117.6 g (0.855 moles) Tri ethylamine HCl and 55.2 g (0.85 moles) Sodium azide. Reaction mass was Heated to reflux and maintain till the completion of reaction. After completion of reaction, the reaction mass was cooled and added 100 ml Toluene followed by Sodium hydroxide solution. Separated lower Sodium hydroxide layer,added 400 ml water to upper layer and separated lower aqueous layer. Again added 56.7 ml water to upper layer and separated lower aqueous layer. Combined both the aqueous layer and distilled 100-110 ml water. Added same amount of fresh water (100-110 ml), added 21.03 g (0.305 moles) Sodium nitrite solution. Added 3.89 g (0.022 moles) Hydrose and heated to reflux and maintained till the completion of reaction. After completion of reaction, the reaction mass was cooled and added Activated carbon. Filtered and adjusted the pH 3.3-4.3 using dil. HCl. Reaction mass was filtered and slurried in water. Wet solid refluxed in IPA at 80-820C for 1 hr. Reaction mass was cooled and filtered and dried to give 97±4 gm of Losartan base.
Purity (By HPLC): 99.0%
Losartan azide content (By HPLC): 5 ppm

Example-4: Synthesis of Losartan base (Using Sodium sulfide)
Into a 1000 ml flask equipped with a reflux condenser, thermometer and stirrer were placed 100 ml Toluene, 100 g (0.26 moles) compound of formula-II, 117.6 g (0.855 moles) Tri ethylamine HCl and 55.2 g (0.85 moles) Sodium azide. Reaction mass was Heated to reflux and maintain till the completion of reaction. After completion of reaction, the reaction mass was cooled and added 100 ml Toluene followed by Sodium hydroxide solution. Separated lower Sodium hydroxide layer, added 400 ml water to upper layer and separated lower aqueous layer. Again added 56.7 ml water to upper layer and separated lower aqueous layer. Combined both the aqueous layer and distilled 100-110 ml water. Added same amount of fresh water (100-110 ml) and further added 21.03 g (0.305 moles) of Sodium nitrite solution. Added 1.75 g (0.022 moles) of Sodium sulfide, heated the reaction mass to reflux and maintained till the completion of reaction. After completion of reaction, the reaction mass was cooled and added Activated carbon. Filtered and adjusted the pH 3.3-4.3 using dil. HCl. Reaction mass was filtered and slurried in water. Wet solid was refluxed in IPA at 80-820C for 1 hr, the reaction mass was cooled and filtered and dried to give 97±4 gm of Losartan base.
Purity (By HPLC): 99.0%
Losartan azide content (By HPLC): 4 ppm

Example-5: Synthesis of Losartan base (Using Zinc)
Into a 1000 ml flask equipped with a reflux condenser, thermometer and stirrer were placed 100 ml Toluene, 100 g (0.26 moles) compound of formula-II, 117.6 g (0.855 moles) Tri ethylamine HCl and 55.2 g (0.85 moles) Sodium azide. Reaction mass was Heated to reflux and maintained till the completion of reaction. After completion of reaction, the reaction mass was cooled and added 100 ml Toluene followed by Sodium hydroxide solution. Separated lower Sodium hydroxide layer, added 400 ml water to upper layer and separated lower aqueous layer. Again added 56.7 ml water to upper layer and separated lower aqueous layer. Combined both the aqueous layers and distilled 100-110 ml water. Added same amount of fresh water (100-110 ml);added 21.03 g (0.305 moles) Sodium nitrite solution and Activated carbon at 45-500C. The reaction mass was stirred for 1 hr and filtered. Added 5.16 g (0.079 moles) Zinc to the filtrate. Reaction mass was stirred at room temperature till the completion of reaction. After completion of reaction, thereaction mass was filtered. pH of reaction mass was adjusted to 3.3-4.3 using dil. HCl. Reaction mass filtered and slurried in water. Wet solid refluxed in IPA at 80-820C for 1 hr. Reaction mass was cooled and filtered and dried to give 97±4 gm of Losartan base
Purity (By HPLC): 99.0%
Losartan azide content (By HPLC): 5 ppm

Example-6: Synthesis of Losartan Potassium
Into a 1000 ml flask equipped with a reflux condenser, thermometer and stirrer were placed 300 ml methanol, 15.4 g (0.26 moles) potassium hydroxide, 100 g (0.236 moles) Losartan base. Reaction mass was heated to 40-450C. Added 8 g of Activated Carbon and 1.23 g (0.007 moles) of Hydrose. Reaction mass was maintained for 1 hr at 40-500C. Reaction mass was filtered and washed with 60 ml Methanol. The filtrate was again treated with 8 g Activated Carbon at 40-500C and filtered. Distilled Methanol completely from the reaction mass under vacuum at 50-550C. Added 120 ml IPA and distilled to remove Methanol Azeotropically. 120 ml IPA added again and distilled completely to remove Methanol. Added 200 ml Acetone into solid residue and heated to reflux for 1 hr. Reaction mass was cooled to -5 to 50C and stirred for 1 hr. Reaction mass was filtered and washed with chilled acetone and dried to give 90 g of Losartan potassium.
Purity (By HPLC): 99.0%
Losartan azide content (By LCMS): 2 ppm