DESC:FIELD OF THE INVENTION:
The present invention relates to a process for the preparation of highly pure Valsartan which is free from toxic nitroso amine impurities.

BACKGROUND OF THE INVENTION:
Valsartan is chemically known as N-(1-oxopentyl)-N-[[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-L-valine (formula-1). 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.

Formula-1
Valsartan and its pharmaceutically acceptable salts are disclosed in US5399578. US’578 discloses the process for preparing Valsartan which comprises the reaction of L-valine methyl ester hydrochloride with 4-bromo methyl-2’-cyanobiphenyl to produce 4-[(2’-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester which reacts with valeryl chloride to give N-[(2’-cyanobiphenyl-4-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’578 is shown in scheme 1.

Scheme-1
Valsartan and/or its intermediates are disclosed in various references including U.S. Patent Nos. 5,965,592, 5,260,325, 6,271,375, WO 02/006253, WO 01/082858, WO 99/67231 , WO 97/30036 and Peter Buhlmayer, et. al., Bioorganic & Medicinal Chemistry Letters, Vol. 4 (1), pp 29-34, 1994.

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;

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 4-(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 4-(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 4-(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.

SUMMARY OF THE INVENTION:
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 4-(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 4-(methyl(nitroso)amino)butanoic acid (NMBA) impurities comprising the steps of;
a) Treating crude Valsartan dissolved in an organic solvent with aqueous sodium hydrosulphite solution;
b) Separating the organic layer obtained from step (a) followed by treatment with water and Sodium chloride solution sequentially;
c) Distilling out the organic solvent completely followed by dissolving residue in methanol followed by treating with alcoholic sodium hydroxide solution, and distilling out methanol completely;
d) Dissolving residue obtained from step (c) in mixture of methanol and ethyl acetate, cooled to effect precipitating of sodium salt of Valsartan;
e) acidifying the sodium salt of Valsartan solution obtained in step (d) with conc. HCl followed by extracting Valsartan into ethyl acetate; and
f) Treating the ethyl acetate solution with activated charcoal, followed by cooling the filtrate to isolate the pure Valsartan.

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

DETAILED DESCRIPTION OF THE PRESENT 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.

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 4-(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 4-(methyl(nitroso)amino) butanoic acid (NMBA) impurities which process comprising the steps of;
a) Treating crude Valsartan dissolved in an organic solvent with aqueous sodium hydrosulphite solution;
b) Separating the organic layer obtained from step (a) followed by treatment with water and Sodium chloride solution sequentially;
c) Distilling out the organic solvent completely followed by dissolving residue in methanol and treating with alcoholic sodium hydroxide solution; distilling out methanol completely;
d) Dissolving residue obtained from step (c) in mixture of methanol and ethyl acetate, cooled to effect precipitating of sodium salt of Valsartan;
e) acidifying the sodium salt of Valsartan solution obtained in step (d) with conc. HCl followed by extracting Valsartan into ethyl acetate; and
f) Treating the ethyl acetate solution with activated charcoal, followed by cooling the filtrate to isolate the pure Valsartan.

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, ester solvents, etc.
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 10 to -10°C.

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;
a) Treating crude Valsartan dissolved in an organic solvent with aqueous sodium hydrosulphite solution;
b) Separating the organic layer obtained from step (a) followed by treatment with water and Sodium chloride solution sequentially;
c) Distilling out the organic solvent completely followed by dissolving residue in methanol and treating with alcoholic sodium hydroxide solution; distilling out methanol completely;
d) Dissolving residue obtained from step (c) in mixture of methanol and ethyl acetate, cooled to effect precipitating of sodium salt of Valsartan;
e) acidifying the sodium salt of Valsartan solution obtained in step (d) with conc. HCl followed by extracting Valsartan into ethyl acetate; and
f) Treating the ethyl acetate solution with activated charcoal, followed by cooling the filtrate to isolate the pure Valsartan.

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 4-(methyl(nitroso)amino)butanoic acid (NMBA) impurities, which comprises the steps of;
(a) Treating crude Valsartan dissolved in an organic solvent with aqueous sodium hydrosulphite solution;
(b) Separating the organic layer obtained from step (a) followed by treatment with water and Sodium chloride solution sequentially;
(c) Distilling out the organic solvent completely followed by dissolving residue in methanol and treating with alcoholic sodium hydroxide solution, distilling out methanol completely; and
(d) Dissolving residue obtained from step (c) in mixture of methanol and ethyl acetate, cooled to effect precipitating of disodium salt of Valsartan.
The organic solvent used to dissolve crude valsartan while treating with aqueous sodium hydrosulphite solution is selected from hydrocarbon solvents, halogenated hydrocarbon solvents, ester solvents, etc.
The process for the preparation of highly pure Valsartan is depicted in the Scheme-2 below.
Scheme 2

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 3 and Scheme 4 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.
Scheme 3

Scheme 4

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.

EXAMPLES
Example-1:
Crude Valsartan (10 gm) is dissolved in Dichloromethane (150 ml) and charged aqueous solution of sodium hydrosulfite (80 ml). Stirred the reaction mass for 30 min. 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 0°C 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 2.5 to 3.5. 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 0°C. 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.
Impurity Initial After purification using Sodium Hydrosulfite
NDMA 0.49 ppm 0.04 ppm
NDEA 0.41 ppm 0.03 ppm

Example-2:
Crude Valsartan (10 gm) is dissolved in Ethyl acetate (150 ml) and charged aqueous solution of sodium hydrosulfite (80 ml). Stirred the reaction mass for 30 min. 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 0°C 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 2.5 to 3.5. 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 0°C. 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.
Impurity Initial After purification using Sodium Hydrosulfite
NDMA 0.49 ppm 0.03 ppm
NDEA 0.41 ppm 0.04 ppm

Example-3:
Crude Valsartan (10 gm) is dissolved in Dichloromethane (150 ml) and charged aqueous solution of sodium hydrosulfite (80 ml). Stirred the reaction mass for 30 min. 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 0°C 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 2.5 to 3.5. 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 0°C. 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.
Impurity Initial After purification using Sodium Hydrosulfite
NDMA 1.0 ppm 0.03 ppm
NDEA 0.8 ppm 0.07 ppm

Example-4:
Crude Valsartan (10 gm) is dissolved in Ethyl acetate (150 ml) and charged aqueous solution of sodium hydrosulfite (80 ml). Stirred the reaction mass for 30 min. 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 0°C 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 2.5 to 3.5. 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 0°C. 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.
Impurity Initial After purification using Sodium Hydrosulfite
NDMA 1.0 ppm 0.05 ppm
NDEA 0.8 ppm 0.04 ppm

Example-5:
Crude Valsartan (10 gm) is dissolved in Dichloromethane (150 ml) and charged aqueous solution of sodium hydrosulfite (80 ml). Stirred the reaction mass for 30 min. 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 0°C 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 2.5 to 3.5. 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 0°C. 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.
Impurity Initial After purification using Sodium Hydrosulfite
NDMA 5.1 ppm 0.26 ppm
NDEA 4.5 ppm 0.18 ppm

Example-6:
Crude Valsartan (10 gm) is dissolved in Ethyl acetate (150 ml) and charged aqueous solution of sodium hydrosulfite (80 ml). Stirred the reaction mass for 30 min. 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 0°C 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 2.5 to 3.5. 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 0°C. 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.
Impurity Initial After purification using Sodium Hydrosulfite
NDMA 5.0 ppm 0.11 ppm
NDEA 5.0 ppm 0.13 ppm

Example-7:
Crude Valsartan (10 gm) is dissolved in Ethyl acetate (150 ml) and charged aqueous solution of sodium hydrosulfite (80 ml). Stirred the reaction mass for 30 min. 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 0°C and white solid was precipitated out. Filtered and dried to obtain disodium salt of Valsartan (8.5 gm) having nitrosoamine impurities well below the limit of quantification.

Method of Analysis of Pure Valsartan and disodium salt of Valsartan by HPLC
Chromatographic Conditions:

Instrument HPLC (Make–ThermoUltima 3000) equipped with UV detector or equivalent.
HPLC System Gradient
Mobile phase-A Buffer
Mobile phase-B Acetonitrile
Mobile phase-C Methanol
Column YMC-Pack Pro C18/S-5µm/12nm; 250mm x 4.6mm x 5µ or Equivalent
Wavelength 225 nm
Flow rate 1.0 ml/min.
Column Oven 40 °C
Injection Volume 300 µL
Autosampler temp. 10°C
Run time 60.0 min.
Diluent Only Buffer solution.
,CLAIMS:1. 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 4-(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.

2. The 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 4-(methyl(nitroso)amino)butanoic acid (NMBA) impurities, as claimed in claim 1 comprising the steps of;
(a) Treating crude Valsartan dissolved in an organic solvent with aqueous sodium hydrosulphite solution;
(b) Separating the organic layer obtained from step (a) followed by treatment with water and Sodium chloride solution sequentially;
(c) Distilling out the organic solvent completely followed by dissolving residue in methanol and treating with alcoholic sodium hydroxide solution, distilling out methanol completely;
(d) Dissolving residue obtained from step (c) in mixture of methanol and ethyl acetate, cooled to effect precipitating sodium salt of Valsartan;
(e) acidifying the sodium salt of Valsartan solution obtained in step (d) with conc. HCl followed by extracting Valsartan into ethyl acetate; and
(f) Treating the ethyl acetate solution with activated charcoal, followed by cooling the filtrate to isolate the pure Valsartan.

3. The process as claimed in claim 1, wherein, the organic solvent used in step a) is selected from hydrocarbon solvents, halogenated hydrocarbon solvents, ester solvents, etc.

4. The process as claimed in claim 3, wherein, the solvent is halogenated hydrocarbon solvent selected from methylene dichloride, ethylene dichloride and chloroform.

5. The process as claimed in claim 3, wherein, the solvent is an ester solvent selected from ethylacetate, Propyl Acetate and isobutylacetate.

6. The process as claimed in claim 1, wherein, the cooling temperature of the process steps d) and f) to affect the precipitation of Valsartan or its salt is in the range of -10 to +10°C.

7. The process for the preparation of disodium salt 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 4-(methyl(nitroso)amino)butanoic acid (NMBA) impurities, as claimed in claim 1 comprising the steps of;
(a) Treating crude Valsartan dissolved in an organic solvent with aqueous sodium hydrosulphite solution;
(b) Separating the organic layer obtained from step (a) followed by treatment with water and Sodium chloride solution sequentially;
(c) Distilling out the organic solvent completely followed by dissolving residue in methanol and treating with alcoholic sodium hydroxide solution, distilling out methanol completely; and
(d) Dissolving residue obtained from step (c) in mixture of methanol and ethyl acetate, cooled to effect precipitating of disodium salt of Valsartan.

8. The process as claimed in claim 1, wherein, the organic solvent used in step a) is selected from hydrocarbon solvents, halogenated hydrocarbon solvents, ester solvents, etc.