FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
&
THE PATENT RULES, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
PROCESS FOR PREPARING VALSARTAN"
We, CADILA HEALTHCARE LIMITED, a company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Road, Ahmedabad-380015, Gujarat, India
The following specification describes the invention.
1

FIELD OF THE INVENTION
The present invention relates to the process of preparation of amorphous valsartan substantially free from residual solvent and D-valsartan. The present invention also relates to process for preparation of valsartan substantially free from tin and azide content. BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
Valsartan, also known as (S)--N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl- )bi phenyl-4-ylmethyl]-amine, has the following structure of formula-I:

and is marketed as the free acid under the name DIOVAN. DIOVAN is prescribed as oral tablets in dosages of 40 mg, 80 mg, 160 mg and 320 mg of valsartan.
Valsartan and/or its intermediates are disclosed in various references, including: U.S. Pat. Nos. 5,399,578, 5,965,592, 5,260,325, 6,271,375, WO 02/006253, WO 01/082858, WO 99/67231, WO 97/30036, Peter Buhlmayer, et. al., Bioorgan. & Med. Chem. Let., 4(1) 29 34 (1994), Th. Moenius, et. al., J. Labelled Cpd. Radiopharm., 43(13) 1245 1252 (2000), and Qingzhong Jia, et. al., Zhongguo Yiyao Gongye Zazhi, 32(9) 385 387 (2001).
Valsartan is an orally active specific angiotensin II antagonist acting on the ATI receptor subtype. Valsartan is prescribed for the treatment of hypertension. U.S. Pat. No. 6,395,728 is directed to use of valsartan for treatment of diabetes related hypertension. U.S. Pat. Nos. 6,465,502 and 6,485,745 are directed to treatment of lung cancer with valsartan. U.S. Pat. No. 6,294,197 is directed to solid oral dosage forms of valsartan.
The synthesis of valsartan is discussed, inter alia, in U.S. Pat. No. 5,399,578. In the synthesis disclosed therein, the final synthetic step (exclusive of work-up and purification)

2

involves the reaction of a cyano group on the biphenyl ring with an azide, for example, tributyl tin azide. The reaction scheme of the '578 patent is as follows in Scheme-1:

■ ■
Peter Buhlmayer, et. al., Bioorgan. & Med. Chem. Let., 4(1) 29 34 (1994).
Another paper, Qingzhong Jia, et. al., Zhongguo Yiyao Gongye Zazhi, 32 (9) 385 387 (2001), discloses a synthesis scheme for valsartan as follows Scheme-2:

3

The formation of tetrazole derivatives includes use of metal reagents as tributyltin chloride or zinc chloride as disclosed herein above. The use of sodium azide in combination with tributyltin chloride results in the formation of tributyltin azide as a useful source for conversion of nitrile to tetrazole in sartans like valsartan. Thus valsartan prepared by using above technique is resulting in formation of metal impurities and contaminated with tin and azide byproducts.
U.S. Patent No. 5,399,578 discloses the process for the condensation of halogenated biphenyl compounds with valine derivatives preferably in anhydrous, solvent or solvent mixture, for example in a carboxamide, for example formamide or dimethylformamide, a halogenated hydrocarbon, for example methylene dichloride, carbon tetrachloride or
4

chlorobenzene, a ketone for example acetone, cyclic ethers, for example tetrahydrofuran, an ester for example ethyl acetate, or a nitrile, for example acetonitrile, or in mixtures thereof, if desired at reduced or elevated temperature, for example in a temperature from about -40°C to about +100°C, and if desired under an inert gas atmosphere, for example a nitrogen atmosphere.
The inventors of the present inventions has found that the patent US '578 doesn't exemplify the specific conditions for the condensation of halogenated biphenyl compounds with valine derivative at lower temperature.
U.S. Patent No. 7,199,144 B2 discloses a process for preparing valsartan containing less than about 5000 ppm residual solvent, comprising of providing valsartan containing less than about 10% organic solvent by weight and triturating in water, or contacting the valsartan with humid air in a fluidized bed drier, or maintaining the valsartan at a temperature of from about 5 to about 60°C, under pressure of less than about 30 mmHg for a period of from about 1 to 5 days, and recovering the valsartan containing less than about 5000 ppm residual solvent.
The present invention provides a process for preparation of N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester hydrochloride in high yield and better purity. The process of preparation of N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester hydrochloride, an important precursor for the preparation of valsartan substantially free from tin and azide is also within the scope of the invention.
There is a need in the art for an improved synthetic process for the preparation of valsartan substantially free from metal impurities having low level of tin content and azide content.
The product mixture of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and by-products of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product mixture. At certain stages during processing of an API, such as Valsartan, it must be analyzed for purity, typically, by HPLC or TLC analysis, to determine if it is suitable for continued processing and, ultimately, for use in a pharmaceutical product. The API need not be absolutely pure, as absolute purity is a theoretical ideal that is typically unattainable. Rather, purity standards are set with the intention of ensuring that an API is as free of impurities as possible, and, thus, is as safe as possible for clinical use. As discussed above, in the United States, the Food and Drug Administration guidelines recommend that the amounts of some impurities be limited to less than 0.1 percent.
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Generally, side products, by-products, and adjunct reagents (collectively "impurities") are identified spectroscopically and/or with another physical method, and then associated with a peak position, such as that in a chromatogram, or a spot on a TLC plate. (Strobel p. 953, Strobel, H. A.; Heineman, W. R., Chemical Instrumentation: A Systematic Approach, 3rd ed. (Wiley & Sons: New York 1989)). Thereafter, the impurity can be identified, e.g., by its relative position in the chromatogram, where the position in a chromatogram is conventionally measured in minutes between injection of the sample on the column and elution of the particular component through the detector. The relative position in the chromatogram is known as the "retention time."
As is known by those skilled in the art, the management of process impurities is greatly enhanced by understanding their chemical structures and synthetic pathways, and by identifying the parameters that influence the amount of impurities in the final product.
Thus, there is a need in the art for Valsartan having a low level of metal impurities through an improved process and identification the contamination of the same by useful calorimety techniques.
The inventors of the present invention has found a process for the preparation of amorphous valsartan substantially free from residual solvent. Also, the present invention provides a process for the preparation of valsartan substantially free from D-Valsartan. The new process for purification valsartan enables to prepare valsartan substantially free from tin and azide at the final stage so as to ensure purity of valsartan sufficient enough from regulatory point of view as well as for clinical use. This would alleviates the hitherto problems associated with prior art or atleast provide an useful alternative. OBJECTS OF INVENTION:
It is an object of the present invention to provide a process for preparing amorphous valsartan substantially free residual solvents.
It is also an object of the present invention to provide a process for preparing amorphous valsartan substantially free from tin and azide.
It is further object of the present invention to provide a process for the preparation of N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester hydrochloride, an important precursor for the preparation of valsartan substantially free from tin and azide.
Further object of the present invention is to provide a novel process for preparing Valsartan which is cost effective, eco-friendly, non-hazardous and applicable for large scale productions.
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SUMMARY OF INVENTION
According to the first embodiment of the present invention, there is provided a process for preparation of amorphous valsartan substantially free from residual solvent comprising of:
a) providing the wet-cake of valsartan having less than about 3000 ppm of residual solvent;
b) treating with suitable organic solvent at about 0°C to about 25°C;
c) filtering amorphous valsartan;
d) maintaining the valsartan at a temperature from about 10°C to about 60°C at pressure of about 600 to about 650 mmHg until substantially free from residual solvent;
e) optionally sieving the product with 20 mesh size filter during maintenance as in step (d); and
f) recovering amorphous valsartan substantially free from residual solvent.
It is also important aspect of the present invention to provide, a process for preparation of amorphous valsartan substantially free from D-Valsartan comprising of:
a) hydrolyzing valsartan methyl ester with a strong base in a suitable organic solvent;
b) extracting aqueous layer with aromatic hydrocarbon and/or halogenated hydrocarbon;
c) heating the reaction mixture at 40°C to 45°C;
d) gradually cooling to 5°C to 10°C;
e) filtering amorphous valsartan with residual solvent less than about 3000 ppm;
g) maintaining the valsartan at a temperature from about 10°C to about 60°C at pressure of
about 600 to about 650 mmHg until substantially free from residual solvent; and
h) isolating amorphous valsartan substantially free from D-Valsartan.

comprising:
7
According to another embodiment of the present invention, there is also provided a process for preparation of N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester, hydrochloride of formula (III)

a) treating 4'-(bromomethyl)-2-cyanobiphenyl of formula (V) with L-valine methyl ester hydrochloride of formula (IV) in molar equivalent of about 1:1 to about 1:1.5 at about 40°C to about 45°C in presence of about 1.3 to about 1.8 molar equivalent of base in suitable organic solvent and isolating the compound of formula (III).

The inventors of the present invention surprisingly found that condensation of formula (V) with compound of formula (IV) at lower temperature preferably at 40°C to 45°C in presence of 1.3-1.8 equivalent of base provides better yield and high purity of compound of formula (III) as compared to use of 3.0 to 3.5 of base as per the process disclosure of US 5,399,578. Overall the present invention provides the compound of formula (III) with better purity and high yield with the formation of lesser impurities and unreacted starting materials.
Preferably, 4'-(bromomethyl)-2-cyanobiphenyl of formula (V) is reacted with L-valine methyl ester hydrochloride of formula (IV) in molar equivalent of about 1:1 to about 1:1.5 at about 40°C to about 45°C in presence of about 1.3 to about 1.8 molar equivalent of base in suitable organic solvent to provide N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester, hydrochloride of formula (III), which is isolated by treatment of reaction mixture with another organic solvent at about 35°C to 45°C and separating the organic layer. Aqueous hydrochloric acid is added in organic layer to adjust the acidic pH 1-2, followed by cooling to precipitate N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester, hydrochloride of formula (III).
In one of the embodiment, the invention provides the process of providing composition of methyl ester of valsartan and byproducts substantially free from azide content comprising the steps of:
a) providing a composition containing methyl ester of valsartan and byproducts containing azide in an organic solvent;
b) treating organic layer as obtained in step a with aqueous solution of sodium nitrite at 5°C to 10°C;
c) adjusting the pH less than 2.5 by cone. HC1;
d) separating the organic layer;
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e) treating the organic layer with 5% sodium carbonate solution till the pH of the aqueous layer is 6.0 to about 7.0; and
f) separating the organic layer containing composition of methyl ester of valsartan and byproducts substantially free from azide.
In another embodiment, the invention provides the process of providing composition of alkali metal salt of valsartan and byproducts substantially free from metal impurities comprising of:
a) providing the composition of methyl ester of valsartan and byproducts in an organic solvent;
b) adding aqueous sodium hydroxide solution with stirring;
c) maintaining the reaction mixture at 40°C to about 45°C for sufficient period of time to hydrolyze Valsartan methyl ester;
d) separating the aqueous layer and removing the organic layer containing metal impurities;
e) treating separated aqueous layer with suitable organic solvent;
f) maintain the reaction mixture at about 35°C to about 45°C for about 60 min;
g) optionally adjusting the pH of the aqueous layer from about 10.0 to 10.5 with dil. HC1;
h) repeating the step e and step f till the aqueous layer is substantially free from metal
impurities; and i) separating the aqueous layer containing composition of alkali metal salt of valsartan and
byproducts substantially free from metal impurities.
In another embodiment, the invention provides a process for preparing valsartan substantially free from azide and metal impurities comprising of:
a) providing composition of alkali metal salt of valsartan and byproducts substantially free from azide and metal impurities in form of aqueous layer;
b) treating the aqueous layer with suitable organic solvent;
c) adjusting the pH of the reaction mixture less than about 4.0 by dil. HC1;
d) maintaining the reaction mixture at about 30°C to 35°C for about 60 min;
e) separate the organic layer and cool to about 20°C to 25°C;
f) treating the organic layer with 10% sodium carbonate solution till the pH is more than about 8.0;
g) repeat the step b and step c;
h) wash the separated organic layer with water;
i) concentrate the organic layer to half and treat with suitable organic solvent at about 40°C
to about 45°C for 30 min; j) cool the reaction mixture to about 15°C to about 20°C to precipitate the product;
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k) filter the product and slurry wash the wet cake with suitable Cs-Cg hydrocarbon; and 1) isolate vaisartan substantially free from azide and metal impurities.
In another embodiment, the invention provides a process for preparing vaisartan having HPLC purity greater than or equal to 99%, preferably 99.5% and chiral purity by HPLC greater than 99%, preferably 99.5%.
Thus, it is one of the embodiment of the present invention to provide a process for preparation of vaisartan in amorphous form comprising of:
a) providing crude vaisartan having HPLC purity not more than 99% and chiral purity not more than 98%;
b) treatment with a suitable organic solvent at about 60°C to 65°C to obtain clear solution;
c) maintain the reaction mixture for about 45 min;
d) gradual cool the reaction mixture to about 25°C to about 30°C in 90 min to precipitate the product;
e) optionally seeding the reaction mixture with standard sample of amorphous vaisartan;
f) filter the product and wash with chilled organic solvent;
g) isolate vaisartan having HPLC purity greater than 99% and chiral purity greater than 99%;
h) optionally treating vaisartan obtained in step g with suitable organic solvent and repeat
the step b and step c; i) optionally distill organic solvent to obtain amorphous vaisartan.
In a further embodiment, the invention provides vaisartan produced by the process of the invention.
Another embodiment, the invention provides vaisartan not having detectable level of azide impurities.
Another embodiment, the invention provides vaisartan substantially free from azide and metal impurities.
A further embodiment, the invention provides vaisartan substantially free from azide and tin impurities.
BRIEF DESCRIPTION OF FIGURES:
A preferred embodiment of the invention will now be described, by way of example only, with reference to the accompaying figures in which: FIG.l: HPLC Chromatogram of related substance of Vaisartan FIG.2: Chiral HPLC Chromatogram of (S)-Vaisartan related to (R)-Isomer FIG.3: HPLC purity of Vaisartan FIG.4: Table for analysis of Tin Content in Vaisartan
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FIG.5: Chromatogram of Standard Sample for Azide Content
FIG.6: Chromatogram of Sample of Valsartan for Azide Content
FIG.7: X-ray diffraction pattern of amorphous Valsartan
FIG.8: Chromatogram of Sample of Valsartan relative to D-Valsartan
FIG.9: Chromatogram of Sample of Valsartan relative to residual solvent.
DETAILED DESCRIPTION
Although the invention has been described with reference to a specific example, it will be appreciated by those skilled in the art that the invention can be embodied in many other forms.
The term "substantially free from residual solvent" means the residual solvent present in amorphous valsartan is not more than about 3000 ppm. Preferably the residual solvent refers to the halogenated hydrocarbons like methylene dichloride, ethylene dichloride, chloroform and the like, aromatic hydrocarbons like toluene, xylene and the like, esters like ethyl acetate, isobutyl acetate and the like, aliphatic hydrocarbons like hexane, heptane, cyclohexane etc. Most preferably the term "substantially free from residual solvent" refers to halogenated hydrocarbons like methylene dichloride present in not more than 500 ppm and aliphatic hydrocarbons like cyclohexane present in not more than 3000 ppm residual solvent in amorphous Valsartan.
The term "substantially free from D-Valsartan" means Valsartan obtained by the present process is of particularly high purity. The valsartan tablet level of the D-isomer is 0.26% area by HPLC (USP method) in the prior art. In our sample, we managed to obtain amorphous valsartan with a level of <0.1% by HPLC according to USP, more preferably about 0.4% of the D-isomer.
Thus, for the purpose of this embodiment, wet-cake of amorphous valsartan having less than about 3000 ppm of residual solvent was treated with suitable organic solvent selected from halogenated hydrocarbons like methylene dichloride, ethylene dichloride, aliphatic hydrocarbons like n-hexane, n-heptane, cyclohexane, esters like ethyl acetate, isobutyl acetate and the like, preferably cyclohexane for 1 hour to about 60 hours under vacuum at 600-650 mmHg with optional sieving through 20 mesh size filter and further dried at 25°C to 35°C for further 10.0 hour under vacuum at 600 to 650 mmHg to obtain amorphous valsartan having residual solvent not more than 3000 ppm.
The invention provides valsartan substantially free of metal impurities and other byproducts. Valsartan obtained by the process of the invention is in fact substantially pure, and in particular substantially free from tin and azide derivatives. The expression "substantially pure" means having a HPLC purity equal to or higher than 99% and chiral
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purity equal to or higher than 99%. The expression "substantially free from tin or azide derivatives" means having a content tin less than or equal to 0.2%, preferably below the detectable amount and azide content less than 0.1%, preferably 0.05%, preferably below the detectable amount.
The present invention provides the process of preparation of N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester, hydrochloride of formula (III)

comprising:
reacting 4'-(bromomethyl)-2-cyanobiphenyl of formula (V) with L-valine methyl ester hydrochloride of formula (IV) in molar equivalent of about 1:1 to about 1:1.5 at about 40°C to about 45°C in presence of about 1.3 to about 1.8 molar equivalent of base in suitable organic solvent and isolating the compound of formula (III).

Preferably, 4'-(bromomethyl)-2-cyanobiphenyl of formula (V) is reacted with L-valine methyl ester hydrochloride of formula (IV) in molar equivalent of about 1:1 to about 1:1.5 at about 40°C to about 45°C in presence of about 1.3 to about 1.8 molar equivalent of base in suitable organic solvent to provide N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester, hydrochloride of formula (III), which is isolated by treatment of reaction mixture with another organic solvent at about 35°C to 45°C and separating the organic layer. Aqueous hydrochloric acid is added in organic layer to adjust the acidic pH 1-2, followed by
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cooling to precipitate N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester, hydrochloride of formula (III).
In one of the embodiment, the present invention provides a process for preparation of N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester, hydrochloride of formula (III)

comprising:
a) reacting 4'-(bromomethyl)-2-cyanobiphenyl of formula (V) with L-valine methyl ester hydrochloride of formula (IV) in molar equivalent of about 1:1 to about 1:1.5 at about 40°C to about 45°C in presence of about 1.3 to about 1.8 molar equivalent of base in

suitable organic solvent for sufficient period of time to complete the reaction;
b) treatment of reaction mixture with another organic solvent at about 35°C to 45°C;
c) separate the organic layer;
d) add aqueous hydrochloric acid in organic layer to adjust the acidic pH;
e) cool to 0°C to 5°C; and
f) filter the product and wash with organic solvent to isolate N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester, hydrochloride of formula (III).
The condensation of 4'-(bromomethyl)-2-cyanobiphenyl of formula (V) with L-valine methyl ester hydrochloride of formula (IV) is preferably carried out in molar equivalent of about 1:1 to about 1:1.5, preferably of about 1:1 to about 1:1.25, more preferably about 1:1 to about 1:1.05 at about 40°C to about 45°C in presence of about 1.3 to about 1.8 molar
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equivalent of base in suitable organic solvent for sufficient period of time to complete the reaction.
The suitable bases can be selected from inorganic bases like carbonates, for example alkali metal carbonates or hydrogencarbonates, such as sodium or potassium carbonate or hydrogencarbonate, alkali metal hydroxides, hydrides, amides, alkanolates, di-lower alkylamides, aminoalkylamides or lower alkylsilylamides, lower alkylamines, ammonium hydroxide, and carbocyclic amines in a molar equivalent of about 1.3 to about 1.8, preferably about 1.4 to about 1.6, more preferably from about 1.45 to about 1.55 molar equivalent.
The suitable organic solvent preferably are anhydrous solvent or solvent mixture, for example in a carboxamide, for example formamide or dimethylformamide, a halogenated hydrocarbon, for example methylene dichloride, carbon tetrachloride or chlorobenzene, a ketone for example acetone, cyclic ethers, for example tetrahydrofuran, an ester for example ethyl acetate, or a nitrile, for example acetonitrile, or in mixtures thereof, preferably dimethyl foramide.
The reaction mixture is heated for the sufficient period of time, preferably from about 6 to about 12 hours, more preferably from about 6 to about 8 hours for completion of the reaction. The reaction mixture is treated with another organic solvent as in step b, preferably halogenated hydrocarbon like dichloromethane, chloroform, chlorobenzene etc, C1-C4 ester like ethyl acetate, methyl acetate etc, hydrocarbons like xylene, toluene and the like, preferably toluene.
The acidic pH as in step d is adjusted from about 1 to about 3, more preferably from 1 to about 2.
Preferably, the invention provides the process of providing composition of methyl ester of valsartan and byproducts substantially free from azide content comprising the steps of:
a) providing a composition containing methyl ester of valsartan and byproducts containing azide in an organic solvent;
b) treating organic layer as obtained in step a with aqueous solution of sodium nitrite at 5°C to 10°C;
c) adjusting the pH less than 2.5 by cone. HC1;
d) maintaining the reaction under stirring for about 45 minutes;
e) separating the organic layer and washing with water;
f) treating the organic layer with 5% sodium carbonate solution till the pH of the aqueous layer is 6.0 to about 7.0; and
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g) separating the organic layer containing composition of methyl ester of valsartan and byproducts substantially free from azide.
The process for preparation of composition of methyl ester of valsartan and byproducts containing azide is well disclosed in many publications in particular US 5,399,578, which is incorporated herein as the reference.
The suitable organic solvents for preparing the composition of methyl ester of valsartan and byproducts containing contamination of tin and azide can be selected from the group of benzene, toluene or xylene preferably xylene. Xylene layer is treated with sodium nitrite solution thereby adjusting the pH with cone. HC1 to highly acidic less than 2.5, preferably from about 1.5 to about 2.5, preferably from aboutl.8 to about 2.0. The organic layer is separated and washed with water, preferably hot water at 40°C. The above procedure is optionally repeated for sufficient time so as to obtain composition of methyl ester of valsartan and related byproducts substantially free from azide contaminations.
After completion of the reaction, it is necessary to decompose an excess salt of azide in step (a). As the method of decomposing a salt of azide, a method of decomposition by nitrous acid is preferable. When nitrous acid is used, it is preferable to prepare nitrous acid from a nitrite and an acid.
Specifically, nitrous acid can be prepared in the reaction system by, after completion of the reaction of Step (a), cooling the reaction mixture and adding a nitrite and an acid. Examples of the nitrite include sodium nitride, potassium nitrite, calcium nitride and the like, and sodium nitrite is preferable from the economical standpoint.
In decomposing a salt of azide, it is desirable to add a suitable organic solvent for progressing the decomposition reaction smoothly and suppressing generation of impurities. Examples of the suitable organic solvent include dichloromethane, ethyl acetate, tetrahydrofuran, acetone and the like.
In another embodiment, the invention provides the process of providing composition of alkali metal salt of valsartan and byproducts substantially free from metal impurities comprising of:
a) providing the composition of methyl ester of valsartan and byproducts in an organic solvent;
b) adding aqueous sodium hydroxide solution with stirring;
c) maintaining the reaction mixture at 40°C to about 45°C for sufficient period of time to hydrolyze Valsartan methyl ester;
d) separating the aqueous layer and removing the organic layer containing metal impurities;
e) treating separated aqueous layer with suitable organic solvent;
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f) maintain the reaction mixture at about 35°C to about 45°C for about 60 min;
g) optionally adjusting the pH of the aqueous layer from about 10.0 to 10.5 with dil. HC1;
h) repeating the step e and step f till the aqueous layer is substantially free from metal
impurities; and i) separating the aqueous layer containing composition of alkali metal salt of valsartan and byproducts substantially free from metal impurities.
The suitable organic solvents for preparing the composition of methyl ester of valsartan and byproducts containing contamination of tin and azide can be selected from the group of benzene, toluene or xylene preferably xylene. The organic layer is then subjected to hydrolysis by aqueous solution of sodium hydroxide at about 40°C to 45°C for sufficient period of time i.e. from about 10 hrs to about 16 hours, preferably from about 12 hrs to about 14 hrs.
The aqueous layer separated in step (d) is treated with suitable organic solvent like ethylacetate, dichloromethane etc., preferably dichloromethane and maintaining the reaction mixture for at about 35°C to about 45°C for about 60 min. The above procedure is optionally repeated till the aqueous layer is substantially free from metal impurities and separating the aqueous layer containing alkali metal salt of valsartan preferably valsartan sodium.
In another embodiment, the invention provides a process for preparing valsartan substantially free from azide and metal impurities comprising of:
a) providing composition of alkali metal salt of valsartan and byproducts substantially free from azide and metal impurities in form of aqueous layer;
b) treating the aqueous layer with suitable organic solvent;
c) adjusting the pH of the reaction mixture less than about 4.0 by dil. HC1;
d) maintaining the reaction mixture at about 30°C to 35°C for about 60 min;
e) separate the organic layer and cool to about 20°C to 25°C;
f) treating the organic layer with 10% sodium carbonate solution till the pH is more than about 8.0;
g) repeat the step b and step c;
h) wash the separated organic layer with water;
i) concentrate the organic layer to half and treat with suitable organic solvent at about 40°C
to about 45°C for 30 min; j) cool the reaction mixture to about 15°C to about 20°C to precipitate the product; k) filter the product and slurry wash the wet cake with suitable Cs-Cg hydrocarbon; and 1) isolate valsartan substantially free from azide and metal impurities.
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The suitable organic solvent of step (b) and step (i) can be selected from ethyl acetate, dichloromethane etc, preferably dichloromethane. The suitable C5-C8 hydrocarbon can be selected from pentane, hexane, heptane, cyclohexane etc. preferably cyclohexane.
In another embodiment, the invention provides a process for preparing valsartan having HPLC purity greater than or equal to 99%, preferably 99.5% and chiral purity by HPLC greater than 99%, preferably 99.5%.
Thus, it is one of the embodiment of the present invention to provide a process for preparation of valsartan in amorphous form comprising of:
a) providing crude valsartan having HPLC purity not more than 99% and chiral purity not more than 98%;
b) treatment with a suitable organic solvent at about 60°C to 65°C to obtain clear solution;
c) maintain the reaction mixture for about 45 min;
d) gradual cool the reaction mixture to about 25°C to about 30°C in 90 min to precipitate the product;
e) optionally seeding the reaction mixture with standard sample of amorphous valsartan;
f) filter the product and wash with chilled organic solvent;
g) isolate valsartan having HPLC purity greater than 99% and chiral purity greater than 99%;
h) optionally treating valsartan obtained in step g with suitable organic solvent and repeat
the step b and step c; i) optionally distill organic solvent to obtain amorphous valsartan.
The suitable organic solvent is selected from C1.3 alcohols, C2-4 esters, C3.5 ethers, ketones, C|.5 amides, DMSO, toluene and a mixture thereof with water; preferably ethyl acetate.
The most preferred embodiment of the present invention is to provide process of preparing valsartan substantially free from tin less than about 0.5%, preferably less than about 0.3%, more preferably less than about 0.2% and azide content less than 0.15 %, more preferably less than 0.10%.
The present invention also provides amorphous valsartan with particle size 90% quantile i.e. D(0.9) between about 50 um to about 200 um, preferably between about 75 um to about 175 um and more preferably between about 100 urn to about 150 um when measured by Malvern light scattering measurement instrument.
The present invention further provides the method of detecting and determining the content of tin in valsartan also provides the method of detecting and determining the content of azide in valsartan by HPLC.
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Results of azide content analysis Standard of Azide Sample

No. Ret. Time Min Peak Name Height mS Area mS*min Amount mg/mL Type
1 12.350 Azide 0.170 0.129 0.20 BMB
Total 0.170 0.129 0.20

No. Ret. Time Min Peak Name Height mS Area mS*min AmountUg/mL Type
Not Detected 0.000 0.000 0.000
Total 0.000 0.000 0.000
Results of different Batch Analysis

Batch No. Tests Results
07/VS-API/502/011 AZIDE CONTENT NOT DETECTED
07/VS-API/482/088
07/VS-API/482/124
07/VS-API/482/090
07/VS-API/482/091
Chiral purity by HPLC: Chromatographic conditions:
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Equipment
Column Flow Rate Mobile Phase
Column oven temp. Wavelength Injection Volume Run time

: Shimadzu LC2010C HPLC system equipped with a dual
wavelength UV-VIS detector or equivalent.
: Chiralcel OD-H (250 mm x 4.6 mm, 5mm) or equivalent
: 0.8 ml / minute
: n-hexane: 2-propanol: triflouroacetic acid in the volume ratio
85:15: 0.1. Make adjustments if necessary to meet the system
suitability criteria. :25°C : 230 nm : 10 ul : 25.0 minutes

Related substance by HPLC: Chromatographic conditions:
Equipment : Shimadzu LC2010C HPLC system equipped with a dual
wavelength UV-VIS detector or equivalent.
Column : Vydac ODS (150 mm x 4.6 mm, 4um) or equivalent column.
Flow Rate : 0.4 ml / minute
Mobile Phase : water, Acetonitrile and glacial acetic acid in the volume ratio of
500: 500:1. Make adjustments if necessary to meet the system suitability criteria.
Column oven temp. : 25°C
Wavelength : 225nm
Injection Volume : 10 ml
Run time : 60 minutes
Azide content by HPLC: Chromatographic conditions:
Equipment : Shimadzu LC2010C HPLC system equipped with a dual
wavelength UV-VIS detector or equivalent.
Column : PolymerX RP-1, 100°A column (250 mm x 4.6 mm, 5um) or
equivalent
Flow Rate : 1.0 ml / minute
Mobile Phase : degassed mixture of Buffer and Acetonitrile in the volume ration
of 95:5. Make adjustments if necessary to meet the system
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Having thus described the invention with reference to particular preferred embodiments and illustrative examples, those in the art would appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The Examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to, limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in numerous publications.
Reference Example: Preparation of (S)-N-(l-carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)-biphenyl-4-yl methyl] amine (Valsartan)
N-Valeryl-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester (51.5 kg), tributyl tin chloride (61.9 kg), sodium azide (16.5 kg) were added to xylene (258 lit) and stirred for 1-2 hours at a temperature of 25-35 C then heated the mass to reflux and stirred till the reaction substantially completes. Cool the mass to 25-35°C and 10% sodium hydroxide solution (250 lit.) was added and further stirred for 24-30 hours.
The aqueous layer was separated from the resulting biphasic solution and washed with toluene (52 X 2 lit.). The pH of the aqueous layer was adjusted towards neutral with acetic acid (115 lit. ) and washed with chloroform (52 X 2 lit.). The pH of the aqueous layer was further lowered with acetic acid (20 lit.) and extracted the compound into dichloromethane (220 x 1 + 110 x 1). The combined organic layer was successively washed with water, 5% sodium chloride solution and dried over anhydrous sodium sulphate. The solvent from the reaction solution was completely distilled off and triturated the resulting oily mass with hexane to yield the crude Valsartan, which was recrystallised in dichloromethane followed by ethyl acetate to afford sufficient pure Valsartan, which is having an amorphous pattern by its X-ray diffractogram (Yield: 8.8 kgs).
Example-1: N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester, hydrochloride
32.33 g of L-valine methyl ester hydrochloride was taken in 140 mL of DMF in round bottom flask at 25°C to 35°C. 38.20 g of K2C03 was added to the reaction mixture slowly. 50 g of N-[(2'-cyanobiphenyl-4-yl)methyl bromide was added and the reaction mixture was heated at 40°C to 45°C for 6-7 hrs and reaction was monitored on HPLC/TLC. After the completion of the reaction mixture was treated with toluene and water. The organic layer was separated and acidified with aqueous hydrochloric acid to adjust the pH at about 1-2. The reaction mixture was cooled to 0°C to 5°C. The product was filtered, washed with chilled toluene and dried under vacuum at 60°C to 65°C until moisture was less than 1.0% to obtain 85%-87% N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester, hydrochloride.
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dichloromethane (1021.0 mL) was added and reflux at 40°C to 45°C. The reaction mass was filtered and cooled up to 10°C to 15°C and maintain for 1 hour and gradually cooled to 5°C to 10°C and maintained for 2 hours. The reaction mass was filtered under vacuum and wet cake was washed with dichloromethane (113.0 mL) to obtain technical valsartan wet-cake. The wet-cake was bed washed with cyclohexane (250.0 mL) at 25°C to 35°C.
(c) Drying to Technical Valsartan
Valsartan technical obtained in step (b) was dried at 25°C to 30°C in a fan dryer oven for 6.0 hours. Further the material was dried at 35°C to 40°C in a fan dryer oven for 8 to 10 hours till the LOD was not more than 2%. Dry weight 150.0-155.0 g.
Example-4: Process of preparing Valsartan
Valsartan technical as prepared in example-3 (145.0 gm) was treated with 870.0 mL of dichloromethane at 25°C to 30°C. The reaction mixture was heated at 35°C to 40°C for 1 hour and cooled with stirring up to 25°C to 30°C and maintained for 2 hours. Further it was cooled to 10°C to 15°C and maintained for 1 hour and finally cooled to 5°C to 10°C and maintained for 1 hour. The product was filtered under vacuum and wet cake was washed with chilled dichloromethane (72.5 mL).
Example-5: Drying of Valsartan
The wet-cake of valsartan as prepared in example-4 was dried at 25°C to 35°C for 6.0 hours under vacuum at 600 to 650 mmHg. The material was sieved through 20.0 mesh and further dried at 25°C to 35°C for further 14.0 hour under vacuum at 600 to 650 mmHg. The residual solvent dichloromethane more than 3000.0 ppm, further dry valsartan at 25°C to 35°C for 20.0 hours under vacuum at 600 to 650 mmHg to obtain valsartan with residual dichloromethane not more than 3000.0 ppm.
Example-6: Preparation of amorphous Valsartan
Valsartan with residual dichloromethane less than 3000.0 ppm was treated with cyclohexane (435.0 mL) at 10°C to 15°C and stirred for 10 min. Further, cyclohexane (725.0 mL) was added and reaction mixture was stirred for 3.0 hours at 10°C to 15°C. The product was filtered and washed with cyclohexane and suck dried.
Example-7: Drying of amorphous Valsartan
The wet-cake of amorphous valsartan as prepared example-6 was dried for 4.0 hours under vacuum at 600-650 mmHg. The material was sieved through 20.0 mesh and further dried at 25°C to 35°C for further 10.0 hour under vacuum at 600 to 650 mmHg. The product was further dried at 40°C to 45°C for 6.0 hours under vacuum at 600 to 650 mmHg followed by drying at 50°C to 55°C for 20.0 hours to obtain amorphous valsartan having residual dichloromethane not more than 500.0 ppm and residual cyclohexane not more than 3000.0
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ppm. If not the product was further dried at 55°C to 60°C for 20.0 hours under vacuum at
600-650 mmHg to obtain amorphous valsartan substantially free from residual solvents.
HPLC purity: 99.5-99.8%; Total Impurity: 0.5-0.2 %; CHIRAL Purity: 99.5-99.8%; R-
Isomer: 0.5-0.2%.
Example-8: Determination of Azide Content
Preparation of 0.5 % CUSO4 solution :
Weigh accurately about 500 mg of CUSO4 and transfer it into a 100.0 ml volumetric flask. Add about 15 ml of water and sonicate the flask to dissolve the contents and make the volume up to the mark with water, and mix the contents.
Preparation of Azide standard stock solution:
Weigh accurately about 10 mg of Sodium Azide standard and transfer it into a 100.0 ml volumetric flask. Add about 15 ml of water and sonicate the flask to dissolve the contents and make the volume upto the mark with water, and mix the contents. Transfer 5.0 ml of above stock solution in to 50.0ml volumetric flask and make up to volume with water. Designate this solution Azide standard stock solution. (10 mg/ml Sodium Azide).
Standard preparation:
Pipette 1 ml (10 ppm) of Azide standard stock solution in to a 50 ml colour comparison tube (Nessler cylinder) and add 10 ml of methanol to same colour comparison tube. Add 3.0 ml of water, 0.2 ml of CS2 and 1.5 ml of acetone to the colour comparison tube and mix the contents. Boil the solution for two minutes at 40 °C on water bath. Add 1.0 ml of 0.5 % CUSO4 solution to the same colour comparison tube and mix the contents.
Test preparation:
Weigh accurately about 1 g of the test substance in to a 50 ml colour comparison tube (Nessler cylinder), add 10 ml of methanol to same colour comparison tube and sonicate to dissolve the contents. Add 3.0 ml of water, 0.2 ml of CS2 and 1.5 ml of acetone to the colour comparison tube and mix the contents. Boil the solution for two minutes at 40 °C on water bath. Add 1.0 ml of 0.5 % CuS04 solution to the same colour comparison tube and mix the contents.
Blank preparation:
Add 10 ml of methanol in to a 50 ml colour comparison tube (Nessler cylinder), 3.0 ml of water, 0.2 ml of CS2 and 1.5 ml of acetone to the colour comparison tube and mix the contents. Boil the solution for two minutes at 40 °C on water bath. Add 1.0 ml of 0.5 % CUSO4 solution to the same colour comparison tube and mix the contents.
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Observation:
The color of the solution from the Test Preparation is not more intense than that of the solution from the Standard preparation (0.1% Azide (10 ppm)).
Example-9: Determination of Tin content by TLC:
Reference solution (a):
Weigh accurately about 27.4 mg Tributyl Tin chloride standard into a 100.0 ml volumetric flask. Add about 25 ml dichloromethane to the volumetric flask, mix the contents and make the volume upto the mark with dichloromethane. Designate this solution as Reference solution (a). (100.0 ppm Tributyl Tin chloride)
Reference solution (b):
Transfer 1.0 ml of Reference solution (a) in to a 10.0 ml volumetric flask contents and make the volume upto the mark with dichloromethane Designate this solution as Reference solution (b). (10.0 ppm Tributyl Tin chloride)
A) Preparation of Test solution:
Weigh accurately about 500 mg Valsartan sample into a 5.0 ml volumetric flask. Add about 3 ml methanol to the volumetric flask, sonicate the volumetric flask to dissolve the contents and make the volume upto the mark with methanol. Designate this solution as Test solution. (10% Valsartan)
B) Preparation of Potassium Permanganate solution:
Weigh accurately about 100 mg Potassium Permanganate sample into a 100.0 ml volumetric flask. Add about 50 ml water to the volumetric flask, sonicate the volumetric flask to dissolve the contents and add 2 to 3 drops of sulfuric acid to the same volumetric flask and make the volume upto the mark with water. Designate this solution as Potassium Permanganate solution.
C) TLC system:
TLC Plate: TLC Silica gel 60 F254TLC Plate. (10 x 6 cm)
Mobile phase: Dichloromethane: Methanol: Ammonia (70: 30: 2 v/v).
Application volume: 15 ul of each of Reference solution (a), Reference solution (b) and Test
solutions on the TLC plate.
Development: Saturate the chamber for 20 min with the mobile phase before developing
the TLC. Keep the plate in side the chromatographic chamber, develop the plate over a path
range of about 8 cm.
Drying: Dry the TLC plate in air.
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Detection: Deep the TLC plat in to a 0.1 % Potassium Permanganate solution for 2 minutes
and again deep the TLC plat in to a distilled water
Limit:
Any spot corresponding to Tributyl Tin chloride in the chromatogram obtained with test
solution is not more intense than the spot observed in the chromatogram obtained with
reference solution (b). (10 ppm)
Advantages of the Invention:-
1. The present invention provides a very cost-effective, eco-friendly, non-hazardous and large scale applicable method.
2. The present invention provides valsartan substantially free from tin and azide.
3. The present invention provides process for preparing valsartan having HPLC purity in the range of 99.5-99.8%; total Impurity in the range of 0.5-0.2 %; chiral Purity in the range of 99.5-99.8% and R-Isomer in the range of 0.5-0.2%.
4. The present invention provides a process for the preparation of N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester hydrochloride, an important precursor for the preparation of valsartan substantially free from tin and azide.
5. The present invention provides a process for the preparation of amorphous valsartan substantially free from residual solvent.
6. The present invention also provides a process for the preparation of amorphous valsartan substantially free from D-Valsartan.
Dated this the 27th day of September 2007

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