Method for preparing high-purity valsartan

Abstract

The present invention discloses a method for preparing and purifying valsartan. The method of the present invention can remove toxic nitrosamine impurities and provide substantially pure valsartan.

Description

Field of the Invention

[0001] The present invention relates to a method for preparing high-purity valsartan that does not contain toxic nitrosamine impurities. Background of the Invention

[0003] Valsartan is chemically known as N-(l-valeryl)-N-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-L-valine (Formula-1). Valsartan is a non-peptide, orally active, specific angiotensin II receptor blocker that acts on the AT1 receptor subtype. Angiotensin II antagonists can be used to treat cardiovascular diseases such as hypertension, heart failure, and stroke.

[0004]

[0005] Valsartan and its pharmaceutically acceptable salts are disclosed in US5399578. US'578 discloses a method for preparing valsartan that includes reacting L-valine methyl ester hydrochloride with 4-bromomethyl-2'-cyanobiphenyl to form 4-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester, reacting with valeryl chloride to form N-[(2'-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine methyl ester, reacting with tributyltin azide to form valsartan methyl ester, which is then hydrolyzed under basic conditions to finally obtain valsartan. The synthesis reported in US'578 is shown in Scheme 1.

[0006]

[0007] Scheme-1

[0008] 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 and Medicinal Chemistry Letters, Vol. 4(1), pp. 29-34, 1994.

[0009] The main concern in the reported methods for preparing valsartan in the above prior art is the presence of genotoxic and carcinogenic impurities, such as nitrosamine impurities, in the final product. These impurities are highly toxic in nature. Therefore, there is an urgent need to develop a process for preparing valsartan that can eliminate all harmful nitrosamine impurities and obtain substantially pure valsartan that meets the strict regulatory requirements of health agencies (i.e., the US Food and Drug Administration USFDA and the European Medicines Evaluation Agency EMEA). These toxic nitrosamine impurities are due to side reactions during the synthesis of valsartan or due to the use of certain organic solvents.

[0010] The structures of the toxic nitrosamine impurities are shown below:

[0011]

[0012] Therefore, there is still a need in the art for a method for purifying valsartan that is substantially free of N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosodiisopropylamine (NDIPA), N-nitrosoethylisopropylamine (NEIPA), N-nitrosodibutylamine (NDBA), and 4-(methyl(nitroso)amino)butyric acid (NMBA) impurities.

[0013] Interestingly, the present inventors have discovered a method for preparing high-purity valsartan that is substantially free of N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosodiisopropylamine (NDIPA), N-nitrosoethylisopropylamine (NEIPA), N-nitrosodibutylamine (NDBA), and 4-(methyl(nitroso)amino)butyric acid (NMBA) impurities.

[0014] The present inventors have also discovered a method for purifying valsartan that is substantially free of N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosodiisopropylamine (NDIPA), N-nitrosoethylisopropylamine (NEIPA), N-nitrosodibutylamine (NDBA), and 4-(methyl(nitroso)amino)butyric acid (NMBA) impurities.

[0015] The present inventors have surprisingly found that sodium dithionite, commonly known as Rongalite, plays an important role in removing these toxic impurities from crude valsartan. SUMMARY OF THE INVENTION

[0016] The present invention provides a method for preparing valsartan, which is substantially free of impurities such as N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosodiisopropylamine (NDIPA), N-nitrosoethylisopropylamine (NEIPA), N-nitrosodibutylamine (NDBA), and 4-(methyl(nitroso)amino)butyric acid (NMBA). The method includes treating crude valsartan with a sodium dithionite solution. Treating crude valsartan with sodium dithionite successfully reduces these impurities below the detection limit.

[0017] Accordingly, the present invention provides a method for preparing valsartan that is substantially free of impurities such as N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosodiisopropylamine (NDIPA), N-nitrosoethylisopropylamine (NEIPA), N-nitrosodibutylamine (NDBA), and 4-(methyl(nitroso)amino)butyric acid (NMBA), comprising the following steps:

[0018] a) Treating crude valsartan dissolved in an organic solvent with an aqueous sodium dithionite solution;

[0019] b) Separating the organic layer obtained in step (a) and treating it successively with water and a sodium chloride solution;

[0020] c) Completely distilling off the organic solvent, dissolving the residue in methanol, treating it with an alcoholic sodium hydroxide solution, and completely distilling off the methanol;

[0021] d) Dissolving the residue obtained from step (c) in a mixture of methanol and ethyl acetate and cooling to precipitate sodium valsartan disodium salt;

[0022] e) Acidifying the sodium valsartan disodium salt solution obtained in step (d) with a concentrated HCl solution. Then extracting valsartan into ethyl acetate; and,

[0023] f) Treating the ethyl acetate solution with activated carbon and then cooling the filtrate to isolate pure valsartan.

[0024] Sodium dithionite, commonly known as sodium hydrosulfite, plays an important role in completely removing these toxic impurities. Detailed Description of the Invention

[0025] The present invention will now be described in detail in connection with certain preferred and alternative embodiments, so that its various aspects can be more fully understood and appreciated.

[0026] The present invention provides a method for preparing valsartan, which substantially does not contain impurities such as N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosodiisopropylamine (NDIPA), N-nitrosoethylisopropylamine (NEIPA), N-nitrosodibutylamine (NDBA), and 4-(methyl(nitroso)amino)butyric acid (NMBA). The method includes treating crude valsartan with a sodium dithionite solution to eliminate these impurities to below the detection limit and separating pure valsartan.

[0027] Treating crude valsartan with sodium dithionite according to the present invention has successfully eliminated these impurities to below the quantitation limit.

[0028] Valsartan produced by the method of the present invention meets the requirements of health agencies, namely the USFDA and the EMEA.

[0029] Therefore, the present invention provides a method for preparing valsartan that substantially does not contain impurities such as N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosodiisopropylamine (NDIPA), N-nitrosoethylisopropylamine (NEIPA), N-nitrosodibutylamine (NDBA), and 4-(methyl(nitroso)amino)butyric acid (NMBA). The method includes the following steps:

[0030] a) Treating crude valsartan dissolved in an organic solvent with an aqueous sodium dithionite solution;

[0031] b) Separating the organic layer obtained in step (a) and treating it successively with water and a sodium chloride solution;

[0032] c) Completely distilling off the organic solvent, dissolving the residue in methanol, treating it with an alcoholic sodium hydroxide solution, and completely distilling off the methanol;

[0033] d) Dissolving the residue obtained from step (c) in a mixture of methanol and ethyl acetate, and cooling to precipitate the disodium salt of valsartan;

[0034] e) Acidifying the solution of the disodium salt of valsartan obtained in step (d) with a concentrated HCl solution. Then extracting valsartan into ethyl acetate; and,

[0035] f) Treating the ethyl acetate solution with activated carbon, and then cooling the filtrate to separate pure valsartan.

[0036] The organic solvent according to the method of step (a) is a solvent that can dissolve crude valsartan, and it can be selected from hydrocarbon solvents, halogenated hydrocarbon solvents, ester solvents, etc.

[0037] In one embodiment, the solvent is a halogenated hydrocarbon solvent selected from dichloromethane, dichloroethane, and chloroform.

[0038] In another embodiment, the solvent is an ester solvent selected from ethyl acetate, propyl acetate, and isobutyl acetate.

[0039] The cooling temperature in process steps d) and f) that affect the precipitation of valsartan or its salt is in the range of 10 to -10 °C.

[0040] In a preferred embodiment, the present invention provides a method for preparing valsartan substantially free of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) impurities, the method comprising the following steps:

[0041] a) Treating crude valsartan dissolved in an organic solvent with an aqueous solution of sodium dithionite;

[0042] b) Separating the organic layer obtained in step (a) and treating it successively with water and a sodium chloride solution;

[0043] c) Completely distilling off the organic solvent, dissolving the residue in methanol, treating it with an alcoholic solution of sodium hydroxide, and completely distilling off the methanol;

[0044] d) Dissolving the residue obtained from step (c) in a mixture of methanol and ethyl acetate and cooling to precipitate disodium valsartan;

[0045] e) Acidifying the disodium valsartan solution obtained in step (d) with a concentrated HCl solution. Then extracting valsartan into ethyl acetate; and,

[0046] f) Treating the ethyl acetate solution with activated carbon and then cooling the filtrate to separate pure valsartan.

[0047] In yet another embodiment, the present invention provides a method for preparing disodium valsartan substantially free of N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosodiisopropylamine (NDIPA), N-nitrosoethylisopropylamine (NEIPA), N-nitrosodibutylamine (NDBA), and 4-(methyl(nitroso)amino)butyric acid (NMBA) impurities, comprising the following steps;

[0048] (a) Treating crude valsartan dissolved in an organic solvent with an aqueous solution of sodium dithionite;

[0049] (b) Separating the organic layer obtained in step (a) and treating it successively with water and a sodium chloride solution;

[0050] (c) Completely distilling off the organic solvent, dissolving the residue in methanol, treating it with an alcoholic solution of sodium hydroxide, and completely distilling off the methanol; and,

[0051] (d) Dissolving the residue obtained from step (c) in a mixture of methanol and ethyl acetate and cooling to precipitate disodium valsartan.

[0052] When treating with an aqueous solution of sodium dithionite, the organic solvent used for dissolving crude valsartan is selected from hydrocarbon solvents, halogenated hydrocarbon solvents, ester solvents, etc.

[0053] The method for preparing high-purity valsartan is described in Scheme 2 below.

[0054] Scheme 2

[0055]

[0056] The creativity of the present invention lies in treating crude valsartan having these toxic nitrosamine impurities with a sodium dithionite solution. After being treated with the sodium dithionite solution, the above-mentioned toxic nitrosamine impurities are reduced to the corresponding hydrazines, as shown in Scheme 3 and Scheme 4. They enter the aqueous medium and are thus easily removed through the water treatment process, thereby obtaining high-purity valsartan that basically does not contain toxic nitrosamine impurities.

[0057] Scheme 3

[0058]

[0059] Scheme 4

[0060]

[0061] The following examples, including preferred embodiments, will be used to illustrate the implementation of the present invention. It should be understood that the details shown are for the purpose of example and for an illustrative discussion of the preferred embodiments of the present invention.

[0062] Example 1:

[0063] Dissolve crude valsartan (10 g) in dichloromethane (150 mL) and add an aqueous solution of sodium dithionite (80 mL). Stir the reaction mixture for 30 minutes. Separate the layers and wash the dichloromethane-containing layer twice with an aqueous solution of sodium dithionite. In addition, the dichloromethane layer is washed with water and sodium chloride solution respectively. Collect the dichloromethane layer and completely distill off dichloromethane. Dissolve the obtained residue in methanol. Add a NaOH solution in methanol to the reaction mixture and completely distill off methanol. Dissolve the obtained residue in a mixture of methanol and ethyl acetate. Cool to 0 °C and precipitate a white solid. Filter and dry to obtain sodium valsartan. Dissolve the sodium salt in water and acidify with concentrated HCl solution to pH 2.5 to 3.5. The product is extracted with ethyl acetate, and the ethyl acetate layer is washed with sodium chloride solution. Completely distill off ethyl acetate, dissolve the obtained residue in ethyl acetate again, and then carbonize. After carbonization, collect the filtrate and cool to 0 °C. Precipitate the white solid, filter and dry in vacuo to obtain pure valsartan with nitrosamine impurities far below the quantification limit.

[0064]

[0065] Example 2:

[0066] Dissolve the crude valsartan (10 g) in ethyl acetate (150 mL) and add an aqueous solution of sodium dithionite (80 mL). Stir the reaction mass for 30 minutes. Separate the layers and wash the ethyl acetate-containing layer twice with the aqueous solution of sodium dithionite. Additionally, wash the ethyl acetate layer with water and sodium chloride solution respectively. Collect the ethyl acetate layer and distill it off completely. Dissolve the resulting residue in methanol. Add a NaOH solution in methanol to this reaction mass and distill off the methanol completely. Dissolve the resulting residue in a mixture of methanol and ethyl acetate. Cool to 0 °C and precipitate a white solid. Filter and dry to obtain valsartan disodium. Dissolve this sodium salt in water and acidify it with concentrated HCl solution to pH 2.5 to 3.5. Extract the product with ethyl acetate, and wash the ethyl acetate layer with sodium chloride solution. Distill off the ethyl acetate completely, dissolve the resulting residue again in ethyl acetate, and then carbonize it. After carbonization, collect the filtrate and cool to 0 °C. Precipitate the white solid, filter and dry it under vacuum to obtain pure valsartan, the nitrosamine impurity of which is far lower than the limit of quantification.

[0067]

[0068] Example 3:

[0069] Dissolve the crude valsartan (10 g) in dichloromethane (150 mL) and add an aqueous solution of sodium dithionite (80 mL). Stir the reaction mass for 30 minutes. Separate the layers and wash the dichloromethane-containing layer twice with the aqueous solution of sodium dithionite. Additionally, wash the dichloromethane layer with water and sodium chloride solution respectively. Collect the dichloromethane layer and distill it off completely. Dissolve the resulting residue in methanol. Add a NaOH solution in methanol to this reaction mass and distill off the methanol completely. Dissolve the resulting residue in a mixture of methanol and ethyl acetate. Cool to 0 °C and precipitate a white solid. Filter and dry to obtain valsartan disodium. Dissolve this sodium salt in water and acidify it with concentrated HCl solution to pH 2.5 to 3.5. Extract the product with ethyl acetate, and wash the ethyl acetate layer with sodium chloride solution. Distill off the ethyl acetate completely, dissolve the resulting residue again in ethyl acetate, and then carbonize it. After carbonization, collect the filtrate and cool to 0 °C. Precipitate the white solid, filter and dry it under vacuum to obtain pure valsartan, the nitrosamine impurity of which is far lower than the limit of quantification.

[0070]

[0071] Example 4:

[0072] Dissolve crude valsartan (10 gm) in ethyl acetate (150 ml) and add an aqueous solution of sodium dithionite (80 ml). Stir the reaction mass for 30 minutes. Separate the layers and wash the ethyl acetate-containing layer twice with an aqueous solution of sodium dithionite. Further, wash the ethyl acetate layer with water and sodium chloride solution respectively. Collect the ethyl acetate layer and distill it off completely. Dissolve the obtained residue in methanol. Add an NaOH solution in methanol to this reaction mass and distill off methanol completely. Dissolve the obtained residue in a mixture of methanol and ethyl acetate. Cool to 0 °C and precipitate a white solid. Filter and dry to obtain valsartan disodium. Dissolve this sodium salt in water and acidify it with concentrated HCl solution to pH 2.5 to 3.5. Extract the product with ethyl acetate and wash the ethyl acetate layer with sodium chloride solution. Distill off ethyl acetate completely, dissolve the obtained residue again in ethyl acetate, and then carbonize. After carbonization, collect the filtrate and cool to 0 °C. Precipitate the white solid, filter and dry it under vacuum to obtain pure valsartan, the nitrosamine impurity of which is far below the quantification limit.

[0073]

[0074] Example 5:

[0075] Dissolve crude valsartan (10 g) in dichloromethane (150 ml) and add an aqueous solution of sodium dithionite (80 ml). Stir the reaction mass for 30 minutes. Separate the layers and wash the dichloromethane-containing layer twice with an aqueous solution of sodium dithionite. Further, wash the dichloromethane layer with water and sodium chloride solution respectively. Collect the dichloromethane layer and distill it off completely. Dissolve the obtained residue in methanol. Add an NaOH solution in methanol to this reaction mass and distill off methanol completely. Dissolve the obtained residue in a mixture of methanol and ethyl acetate. Cool to 0 °C and precipitate a white solid. Filter and dry to obtain valsartan disodium. Dissolve this sodium salt in water and acidify it with concentrated solution HCl to pH 2.5 to 3.5. Extract the product with ethyl acetate and wash the ethyl acetate layer with sodium chloride solution. Distill off ethyl acetate completely, dissolve the obtained residue again in ethyl acetate, and then carbonize. After carbonization, collect the filtrate and cool to 0 °C. Precipitate the white solid, filter and dry it under vacuum to obtain pure valsartan, the nitrosamine impurity of which is far below the quantification limit.

[0076]

[0077] Example 6:

[0078] Dissolve crude valsartan (10 g) in ethyl acetate (150 mL) and add an aqueous solution of sodium dithionite (80 mL). Stir the reaction mixture for 30 minutes. Separate the layers and wash the ethyl acetate layer containing the main product twice with an aqueous solution of sodium dithionite. In addition, wash the ethyl acetate layer with water and sodium chloride solution respectively. Collect the ethyl acetate layer and distill it off completely. Dissolve the resulting residue in methanol. Add a methanol NaOH solution to this reaction mixture and distill off methanol completely. Dissolve the resulting residue in a mixture of methanol and ethyl acetate. Cool to 0 °C and precipitate a white solid. Filter and dry to obtain valsartan disodium with nitrosamine impurities far below the quantification limit. Dissolve this sodium salt in water and acidify it with concentrated HCl solution to pH 2.5 to 3.5. Extract the product with ethyl acetate and wash the ethyl acetate layer with sodium chloride solution. Distill off ethyl acetate completely, dissolve the resulting residue in ethyl acetate again, and then carbonize it. After carbonization, collect the filtrate and cool to 0 °C. Precipitate the white solid, filter and dry it under vacuum to obtain pure valsartan with nitrosamine impurities far below the quantification limit.

[0079]

[0080] Example 7:

[0081] Dissolve crude valsartan (10 gm) in ethyl acetate (150 ml) and add an aqueous solution of sodium dithionite (80 ml). Stir the reaction mixture for 30 minutes. Separate the layers and wash the ethyl acetate layer containing the main product twice with an aqueous solution of sodium dithionite. In addition, wash the ethyl acetate layer with water and sodium chloride solution respectively. Collect the ethyl acetate layer and distill off ethyl acetate completely. Dissolve the resulting residue in methanol. Add a NaOH solution in methanol to this reaction mixture and distill off methanol completely. Dissolve the resulting residue in a mixture of methanol and ethyl acetate. Cool to 0 °C and precipitate a white solid. Filter and dry to obtain valsartan disodium salt (8.5 gm) with nitrosamine impurities far below the quantification limit.

[0082] Method for HPLC analysis of pure valsartan and valsartan disodium salt

[0083] Chromatographic conditions:

[0084]

[0085]

Claims

1. A method for preparing valsartan substantially free of impurities such as N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosodiisopropylamine (NDIPA), N-nitrosoethylisopropylamine (NEIPA), N-nitrosodibutylamine (NDBA), and 4-(methyl(nitroso)amino)butyric acid (NMBA), characterized in that, The method includes: a) Treating the crude valsartan dissolved in an organic solvent with a sodium dithionite solution to remove impurities to below the detection limit; and, b) Separating substantially pure valsartan; The method includes the following steps; (a) Treating the crude valsartan dissolved in an organic solvent with an aqueous sodium dithionite solution; (b) Separating the organic layer obtained in step (a) and treating it successively with water and a sodium chloride solution; (c) Completely distilling off the organic solvent, dissolving the residue in methanol, treating it with an alcoholic sodium hydroxide solution, and completely distilling off the methanol; (d) Dissolving the residue obtained from step (c) in a mixture of methanol and ethyl acetate, and cooling to precipitate valsartan disodium salt; (e) Acidifying the valsartan disodium salt solution obtained in step (d) with a concentrated HCl solution, and then extracting valsartan into ethyl acetate; and, (f) Treating the ethyl acetate solution with activated carbon, and then cooling the filtrate to separate pure valsartan.

2. The method according to claim 1, wherein The organic solvent used in step a) is selected from hydrocarbon solvents, halogenated hydrocarbon solvents, and ester solvents.

3. The method according to claim 2, wherein The solvent is a halogenated hydrocarbon solvent selected from dichloromethane, dichloroethane, and chloroform.

4. The method according to claim 2, wherein The solvent is an ester solvent selected from ethyl acetate, propyl acetate, and isobutyl acetate.

5. The method according to claim 1, characterized in that Wherein, The cooling temperatures in process steps d) and f) that affect the precipitation of valsartan or its salt are in the range of -10 to +10 °C.

6. A method for preparing valsartan disodium substantially free of impurities such as N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosodiisopropylamine (NDIPA), N-nitrosoethylisopropylamine (NEIPA), N-nitrosodibutylamine (NDBA), and 4-(methyl(nitroso)amino)butyric acid (NMBA), characterized in that, Including the following steps; (a) Treating the crude valsartan dissolved in an organic solvent with an aqueous sodium dithionite solution; (b) Separating the organic layer obtained in step (a) and treating it successively with water and a sodium chloride solution; (c) Completely distilling off the organic solvent, dissolving the residue in methanol, treating it with an alcoholic sodium hydroxide solution, and completely distilling off the methanol; and, (d) Dissolving the residue obtained from step (c) in a mixture of methanol and ethyl acetate, and cooling to precipitate the disodium salt of valsartan.

7. The method according to claim 6, wherein The organic solvent used in step a) is selected from hydrocarbon solvents, halogenated hydrocarbon solvents, and ester solvents.

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