Patent Description:
Valsartan is chemically known as N-(<NUM>-oxopentyl)-N-[[<NUM>'-(<NUM>-tetrazol-<NUM>-yl) [<NUM>,<NUM>'-biphenyl]-<NUM>-yl]methyl]-L-valine (formula-<NUM>). Valsartan is a nonpeptide, orally active, and specific angiotensin II receptor blocker acting on the AT1 receptor subtype. Angiotensin II antagonists are useful as therapeutic for cardiovascular complaints such as hypertension, heart failure, stroke.

Valsartan and its pharmaceutically acceptable salts are disclosed in <CIT>. US'<NUM> discloses the process for preparing Valsartan which comprises the reaction of L-valine methyl ester hydrochloride with <NUM>-bromo methyl-<NUM>'-cyanobiphenyl to produce <NUM>-[(<NUM>'-cyanobiphenyl-<NUM>-yl)methyl]-(L)-valine methyl ester which reacts with valeryl chloride to give N-[(<NUM>'-cyanobiphenyl-<NUM>-yl)methyl]-N-valeryl-(L)-valine methyl ester which reacts with tributyltin azide to give Valsartan methyl ester which is then hydrolyzed under alkaline condition to give finally Valsartan. The synthesis reported in US'<NUM> is shown in scheme <NUM>.

Valsartan and/or its intermediates are disclosed in various references including <CIT>, <CIT>,<CIT>, <CIT>, <CIT>, <CIT> , <CIT>, <NPL> and <NPL>).

The major concern about the process for the preparation of Valsartan as reported in the above prior arts is the presence of genotoxic and carcinogenic impurities such as nitroso amine impurities in the end product. These impurities are highly toxic in nature. Therefore, there is an urgent and pressing need to develop a process for the preparation of Valsartan, wherein such process is capable of eliminating all those harmful nitrosamine impurities and to obtain a substantially pure Valsartan which complies with stringent regulatory requirements of health agencies i.e. USFDA and EMEA. These toxic nitroso amine impurities are generated due to side reactions during the synthetic process for the production of valsartan or due to use of certain organic solvents.

The structures of toxic nitroso amine impurities are depicted below;
<CHM>
<CHM>.

Thus, there remains a need in the art for a process for the purification of Valsartan which is substantially free from N-nitrosodimethyl amine (NDMA), N-nitrosodiethyl amine (NDEA), N-nitrosodiisopropyl amine (NDIPA), N-nitroso ethyl isopropyl amine (NEIPA), N-nitroso dibutyl amine (NDBA) and <NUM>-(methyl(nitroso)amino)butanoic acid (NMBA) impurities.

Interestingly, the present inventors have found a process for the preparation of highly pure Valsartan which is substantially free from N-nitrosodimethyl amine (NDMA), N-nitrosodiethyl amine (NDEA) and N-nitrosodiisopropyl amine (NDIPA) N-nitroso ethyl isopropyl amine (NEIPA), N-nitroso dibutyl amine (NDBA) and <NUM>-(methyl(nitroso)amino)butanoic acid (NMBA) impurities.

The present inventors have also found a process for the purification of Valsartan which is substantially free from N-nitrosodimethyl amine (NDMA), N-nitrosodiethyl amine (NDEA) and N-nitrosodiisopropyl amine (NDIPA) N-nitroso ethyl isopropyl amine (NEIPA), N-nitroso dibutyl amine (NDBA) and <NUM>-(methyl(nitroso)amino)butanoic acid (NMBA) impurities.

The present inventors have surprisingly found that Sodium dithionite commonly known as Sodium hydrosulfite or hydrose plays an important role in the removal of these toxic impurities from crude Valsaran.

The present invention provides a process for the preparation of Valsartan which is substantially free from N-nitrosodimethyl amine (NDMA), N-nitrosodiethyl amine (NDEA) and N-nitrosodiisopropyl amine (NDIPA) N-nitroso ethyl isopropyl amine (NEIPA), N-nitroso dibutyl amine (NDBA) and <NUM>-(methyl(nitroso)amino)butanoic acid (NMBA) impurities which process comprises; treating the crude valsartan with sodium hydrosulphite solution. The treatment of crude valsartan with Sodium hydrosulfite or hydrose successfully eliminates these impurities to below detection limit.

Accordingly, the present invention provides a process for the preparation of Valsartan which is substantially free from N-nitrosodimethyl amine (NDMA), N-nitrosodiethyl amine (NDEA) and N-nitrosodiisopropyl amine (NDIPA) N-nitroso ethyl isopropyl amine (NEIPA), N-nitroso dibutyl amine (NDBA) and <NUM>-(methyl(nitroso)amino)butanoic acid (NMBA) impurities comprising the steps of;.

Sodium dithionite commonly known as Sodium hydrosulfite or hydrose plays an important role in complete removal of these toxic impurities.

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.

The present invention provides a process for the preparation of Valsartan which is substantially free from N-nitrosodimethyl amine (NDMA), N-nitrosodiethyl amine (NDEA) and N-nitrosodiisopropyl amine (NDIPA) N-nitroso ethyl isopropyl amine (NEIPA), N-nitroso dibutyl amine (NDBA) and <NUM>-(methyl(nitroso)amino)butanoic acid (NMBA) impurities which process comprises; treating the crude valsartan with sodium hydrosulphite solution to eliminate these impurities to below detection limit and isolating pure valsartan.

The treatment of crude valsartan with Sodium hydrosulfite or hydrose according to the present invention successfully eliminates these impurities to below quantification limit.

The valsartan produced by the process of the present invention meets the requirement of both health agencies i.e. USFDA and EMEA.

Accordingly, the present invention provides a process for the preparation of Valsartan which is substantially free from N-nitrosodimethyl amine (NDMA), N-nitrosodiethyl amine (NDEA) and N-nitrosodiisopropyl amine (NDIPA) N-nitroso ethyl isopropyl amine (NEIPA), N-nitroso dibutyl amine (NDBA) and <NUM>-(methyl(nitroso)amino) butanoic acid (NMBA) impurities which process comprising the steps of;.

The organic solvent according to the process of step a) is a solvent that can solubilize the crude valsartan that may be selected from hydrocarbon solvents, halogenated hydrocarbon solvents, or ester solvents.

In one embodiment, the solvent is halogenated hydrocarbon solvent selected from methylene dichloride, ethylene dichloride, chloroform.

In another embodiment, the solvent is an ester solvent selected from ethyl acetate, Propyl Acetate and isobutyl acetate.

The cooling temperature of the process steps d) and f) to affect the precipitation of Valsartan or its salt is in the range of <NUM> to -<NUM>.

In a preferred embodiment, the present invention provides a process for the preparation of Valsartan which is substantially free from N-nitrosodimethyl amine (NDMA) and N-nitrosodiethyl amine (NDEA) impurities which process comprising the steps of;.

In yet another embodiment, the invention provides a process for the preparation of disodium salt of Valsartan which is substantially free from N-nitrosodimethyl amine (NDMA), N-nitrosodiethyl amine (NDEA), N-nitrosodiisopropyl amine (NDIPA), N-nitroso ethyl isopropyl amine (NEIPA), N-nitroso dibutyl amine (NDBA) and <NUM>-(methyl(nitroso)amino)butanoic acid (NMBA) impurities, which comprises the steps of;.

The organic solvent used to dissolve crude valsartan while treating with aqueous sodium hydrosulphite solution is selected from hydrocarbon solvents, halogenated hydrocarbon solvents, or ester solvents.

The process for the preparation of highly pure Valsartan is depicted in the Scheme-<NUM> below. <CHM>
<CHM>.

The inventiveness of the present invention lies in the treatment of crude valsartan having these toxic nitroso amine impurities with sodium hydrosulphite solution.

The aforementioned toxic nitroso amine impurities when treated with sodium hydrosulphite solution gets reduced into corresponding hydrazine, as shown in Scheme <NUM> and Scheme <NUM> which goes into the aqueous medium and thus easily removed by water work up process to obtain highly pure Valsartan which is substantially free from toxic nitroso amine impurities. <CHM>
<CHM>.

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

Crude Valsartan (<NUM> gm) is dissolved in Dichloromethane (<NUM>) and charged aqueous solution of sodium hydrosulfite (<NUM>). Stirred the reaction mass for <NUM>. separated the layers and Dichloromethane layer containing was washed twice with aqueous sodium hydrosulphite solution. Further, the Dichloromethane layer is washed with water and sodium chloride solution respectively. Collected Dichloromethane layer and distilled off Dichloromethane completely. The residue obtained was dissolved in Methanol. To this reaction mass methanolic NaOH solution was added and methanol is distilled off completely. The residue obtained is dissolved in a mixture of Methanol and Ethyl acetate. Cooled to <NUM> and white solid was precipitated out. Filtered and dried to obtain Disodium Valsartan. This sodium salt was dissolved in water and acidified with conc. HCl up to pH <NUM> to <NUM>. The product is extracted in ethyl acetate and washed ethyl acetate layer with Sodium Chloride solution. Distilled out Ethyl acetate completely and residue obtained was dissolved again in Ethyl acetate followed by charcoalization. Collected the filtrate after charcoalization and cooled to <NUM>. The white solid was precipitate out, filtered and dried under vacuum to get pure Valsartan having nitrosoamine impurities are well below the limit of quantification.

Crude Valsartan (<NUM> gm) is dissolved in Ethyl acetate (<NUM>) and charged aqueous solution of sodium hydrosulfite (<NUM>). Stirred the reaction mass for <NUM>. separated the layers and Ethyl acetate layer containing was washed twice with aqueous sodium hydrosulphite solution. Further, the Ethyl acetate layer is washed with water and sodium chloride solution respectively. Collected Ethyl acetate layer and distilled off completely. The residue obtained was dissolved in Methanol. To this reaction mass methanolic NaOH solution was added and methanol is distilled off completely. The residue obtained is dissolved in a mixture of Methanol and Ethyl acetate. Cooled to <NUM> and white solid was precipitated out. Filtered and dried to obtain Disodium Valsartan. This sodium salt was dissolved in water and acidified with conc. HCl up to pH <NUM> to <NUM>. The product is extracted in ethyl acetate and washed ethyl acetate layer with Sodium Chloride solution. Distilled out Ethyl acetate completely and residue obtained was dissolved again in Ethyl acetate followed by charcoalization. Collected the filtrate after charcoalization and cooled to <NUM>. The white solid was precipitate out, filtered and dried under vacuum to get pure Valsartan having nitrosoamine impurities are well below the limit of quantification.

Crude Valsartan (<NUM> gm) is dissolved in Dichloromethane (<NUM>) and charged aqueous solution of sodium hydrosulfite (<NUM>). Stirred the reaction mass for <NUM>. separated the layers and Dichloromethane layer containing was washed twice with aqueous sodium hydrosulphite solution. Further, the Dichloromethane layer is washed with water and sodium chloride solution respectively. Collected Dichloromethane layer and distilled off completely. The residue obtained was dissolved in Methanol. To this reaction mass methanolic NaOH solution was added and methanol is distilled off completely. The residue obtained is dissolved in a mixture of Methanol and Ethyl acetate. Cooled to <NUM> and white solid was precipitated out. Filtered and dried to obtain Disodium Valsartan. This sodium salt was dissolved in water and acidified with conc. HCl up to pH <NUM> to <NUM>. The product is extracted in ethyl acetate and washed ethyl acetate layer with Sodium Chloride solution. Distilled out Ethyl acetate completely and residue obtained was dissolved again in Ethyl acetate followed by charcoalization. Collected the filtrate after charcoalization and cooled to <NUM>. The white solid was precipitate out, filtered and dried under vacuum to get pure Valsartan having nitrosoamine impurities are well below the limit of quantification.

Crude Valsartan (<NUM> gm) is dissolved in Ethyl acetate (<NUM>) and charged aqueous solution of sodium hydrosulfite (<NUM>). Stirred the reaction mass for <NUM>. Separated the layers and Ethyl acetate layer containing main product was washed twice with aqueous sodium hydrosulphite solution. Further, the Ethyl acetate layer is washed with water and sodium chloride solution respectively. Collected Ethyl acetate layer and distilled off Ethyl acetate completely. The residue obtained was dissolved in Methanol. To this reaction mass methanolic NaOH solution was added and methanol is distilled off completely. The residue obtained is dissolved in a mixture of Methanol and Ethyl acetate. Cooled to <NUM> and white solid was precipitated out. Filtered and dried to obtain disodium salt of Valsartan (<NUM> gm) having nitrosoamine impurities well below the limit of quantification.

Claim 1:
A process for the preparation of Valsartan, represented by formula-<NUM>, which is substantially free from N-nitrosodimethyl amine (NDMA), N-nitrosodiethyl amine (NDEA) and N-nitrosodiisopropyl amine (NDIPA) N-nitroso ethyl isopropyl amine (NEIPA), N-nitroso dibutyl amine (NDBA) and <NUM>-(methyl(nitroso)amino)butanoic acid (NMBA) impurities which process comprises;
a) treating the crude valsartan dissolved in an organic solvent with sodium hydrosulphite solution to eliminate the impurities to below detection limit; and
b) isolating substantially pure valsartan,
wherein the impurities are determined by HPLC/UV.
<CHM>