Background of the Invention Chemically, valsartan is (S)-N- (l-carboxy-2-methylprop-1-yl) N-pentanoyl-N- [2'- (lH-tetrazol-5-yl)-biphenyl-4-ylmethyl] amine, as shown in Formula I, FORMULA I which has been disclosed as having pronounced angiotensin II antagonist activity and is used to treat high blood pressure and cardiac insufficiency.

The synthesis of valsartan has been disclosed, as well as the recrystallization of valsartan from diisopropyl ether after extraction of a reaction mixture with ethyl acetate.

It has been observed that the isolation of valsartan by crystallization from ethyl acetate results in low yield. The use of diisopropyl ether as an antisolvent to obtain valsartan from a solution of ethyl acetate leads to problems associated with filtration and drying. For example, filtration is slow and the material is sticky in nature, resulting in the product turning to a swollen gel caused by trapped solvent. Also, diisopropylether is retained in the material as

residual solvent, which is difficult to remove and requires prolonged drying. The use of diisopropyl ether alone for recrystallization is not effective, as valsartan is insoluble in diisopropyl ether and upon mixing, forms an oily mass.

Accordingly, there remains a need for an improved process of isolating valsartan, which minimizes or eliminates the above problems and is convenient to operate on a commercial scale.

Summary of the Invention Provided herein are processes for isolating valsartan, which comprises: a) providing a solution of valsartan in one or more suitable solvent, b) adding one or more antisolvent to the above solution or adding the above solution to an antisolvent to form a mixture comprising solid valsartan, and c) isolating the solid valsartan having a purity of greater than about 99 %.

In one embodiment, the isolated valsartan has a purity of greater than about 99. 5 %.

In another embodiment, the solution of valsartan can be a reaction mixture from which valsartan is prepared that is used directly as the solution in step a).

The one or more suitable solvent can be tertiary butyl methyl ether, ester, alcohol, nitrile, chlorinated hydrocarbon, dipolar aprotic solvent, cyclic ether or mixtures thereof. The ester can be, for example, ethylacetate, isopropylacetate or mixtures thereof; the alcohol can be, for example, methanol, ethanol, isopropanol and mixtures thereof ; the chlorinated hydrocarbon can be, for example, methylene chloride, ethylenedichloride or mixtures thereof ; the nitrile can be, for example, acetonitrile, benzonitrile or mixtures thereof ; the dipolar aprotic solvent can be for example, dimethylsulfoxide, dimethylformamide or mixtures thereof; and the cyclic ether can be for example, dioxane, tetrahydrofuran or mixtures thereof.

The volume of the one or more suitable solvent can be about 2 to about 10 times by weight of valsartan.

The one or more antisolvent can be diethyl ether, hydrocarbon or mixtures thereof.

The hydrocarbon can be, for example, pentane, hexane, cyclohexane, heptane, petroleum ethers or mixtures thereof. The volume of the one or more antisolvent can be about 2 to about

10 times by weight the volume of the solvent. The one or more antisolvent can be added at a temperature of from about 0 °C to about 50 °C.

In one embodiment, the solution of valsartan can be concentrated by removing a portion of the more than one suitable solvent before adding antisolvent.

The isolating valsartan comprises decanting, filtering or centrifuging the mixture. In one embodiment, the mixture is optionally cooled to about 0 °C to about 25 °C before isolating solid valsartan.

Detailed Description of the Invention Provided herein are processes for isolating valsartan comprising the steps of : a) providing a solution comprising crude valsartan in one or more suitable solvent; b) adding one or more antisolvent to the valsartan solution or adding the valsartan solution to one or more antisolvent, and c) isolating valsartan.

Valsartan isolated in such processes has at least about 99 % purity by HPLC, and in some embodiments, at least about 99.5 % purity by HPLC. Such isolated valsartan exhibits better <BR> <BR> filtration characteristics, e. g. , the isolated valsartan is not as hygroscopic as valsartan isolated by other known methods and does not form a sticky, swollen gel during filtration.

Consequently, filtration of valsartan isolated by processes disclosed herein is faster and more efficient in a commercial scale. In addition, valsartan isolated by the methods disclosed herein provide a more stable compound.

Valsartan can be prepared from methods known to one of ordinary skill in the art, including methods disclosed in U. S. Patent Nos. 5,399, 578 and 6,271, 375, and Chinese Patent Application No. 1,317, 485, which is incorporated herein by reference. The solution of crude valsartan can be formed by dissolving crude valsartan in one or more suitable solvent at ambient temperatures or higher temperatures up to and including reflux temperatures.

Valsartan can also be utilized without isolation; the valsartan solution can be a reaction mixture from which valsartan is prepared, which is used directly as the solution in step a) of the isolation process.

Suitable solvents include tertiary butyl methyl ether, esters, alcohols, nitriles, chlorinated hydrocarbons, dipolar aprotic solvents, cyclic ethers, or mixtures thereof.

Examples of esters include ethylacetate, isopropylacetate or mixtures thereof. Examples of alcohols include methanol, ethanol, isopropanol or mixtures thereof. Examples of nitriles include acetonitrile, benzonitrile or mixtures thereof. Examples of chlorinated hydrocarbons include methylene chloride, ethylene dichloride or mixtures thereof. Examples of dipolar aprotic solvents include dimethylsulfoxide, dimethylformamide or mixtures thereof.

Examples of cyclic ethers include dioxane, tetrahydrofuran and mixtures thereof.

Generally, valsartan can be dissolved in one or more suitable solvent at a concentration of about 2 times w/v to about 10 times w/v at ambient temperatures. The solution can be stirred at temperatures ranging from ambient temperature to reflux temperature before adding the antisolvent. To facilitate quick precipitation of valsartan, the valsartan solution can be advantageously concentrated before the antisolvent is added. This allows for the use of small amounts of antisolvent required to precipitate valsartan in high yields.

Examples of antisolvents include diethyl ether, hydrocarbons or mixtures thereof.

Examples of hydrocarbon include pentane, hexane, cyclohexane, heptane, petroleum ether, or mixtures thereof.

The mixing in step (b), which facilitates the precipitation of valsartan, can be accomplished by the following procedures. In one procedure, the mixture can be formed by adding antisolvent to the valsartan solution obtained in step (a). In another procedure, the mixture can be formed by adding the valsartan solution to the antisolvent.

In some particular embodiments, precipitation can occur from the solution of valsartan even before the addition of the antisolvent, such as when the solution is concentrated or cooled before step (b).

To achieve suitable precipitation in certain embodiments, the total amount of antisolvent added to the solution of valsartan can be at least about 2 times the total amount of the solvent. In other embodiments, the total amount of antisolvent used can be up to about 10

times the total amount of the solvent. Antisolvent can be added at temperatures of from about 0 °C to about 50 °C.

Similar conditions may also be applied for the reverse addition process.

In step (c) of the process, the precipitate of valsartan formed in step (b) can be separated from the mixture by decanting, filtering, centrifuging or using other similar processing methods for separating solids from liquids known to one of ordinary skill in the art, or any combination of such separation methods.

Valsartan can be recovered by optionally cooling the resulting mixture to about 0 °C to 25 °C before filtration followed by drying.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention.

In the following section embodiments are described by way of examples to illustrate the process of invention. However, these are not intended in any way to limit the scope of the present invention. Several variants of this example would be evident to persons ordinarily skilled in the art.

Examples Example 1. Preparation ofN-[(2'-C anobiphen-4-) meth]-N-pentanoyl- (L)-Valine benzyl ester A solution of N-[(2'-Cyanobiphenyl-4-yl) methyl]-(L)-valine benzyl ester hydrochloride (25 g, 57.5 mmol) in dichloromethane (250mL) was treated with diisopropyl ethyl amine (23.8 g, 184.1 mmol) and valeryl chloride (13.86 g, l 15 mmol) at 0-5 °C for 4 hours. The reaction mixture was washed successively with water, 5% sodium bicarbonate solution and 0. 5N hydrochloric acid. The organic layer was then concentrated to yield the title compound as a yellow-colored oil.

Example 2. Preparation of (S)-N- (l-benzylo& : : p n gRg N-F2' biphenyl-4-yl-methyl] amine A mixture of the N- [ (2'-Cyanobiphenyl-4-yl) methyl]-N-valeryl- (L)-valine benzyl ester oil as obtained above, tributyl tinchloride (56.2 g, 172.6 mmol), sodium azide (11.2 g, 172.6 mmol) and tetrabutyl ammonium bromide (2.5 g) in toluene (80 mL) were refluxed for 30 hours. The reaction mixture was then cooled, a solution of acetic acid (12 mL in 25 mL water) was added and the resulting mixture was stirred for 1 hour. The organic layer was separated, concentrated and stirred with a solution of potassium hydroxide (12.8 g in 250 mL water). The aqueous layer was washed with diisopropyl ether, acidified and extracted with ethyl acetate. Ethyl acetate layer was concentrated under reduced pressure to yield the title compound as reddish thick syrupy mass.

Example 3. Preparation of (S)-N- !-N-(l-carboxy-2-methyl-prop-l yl) N pentanoyl-N-t2 (lH tetrazol-5-yl) biphenyl-4-yl-methyl1 amine (Valsartan) Palladium carbon (3gm, 10%) was added to a solution of (S)-N- (1-benzyloxycarbonyl- 2-methyl-prop-1-yl)-N-pentanoyl-N- [2' (1H-tetrazol-5-yl) biphenyl-4-yl-methyl] amine obtained above in methanol (100 mL) and hydrogenated at room temperature. The reaction was monitored by TLC and after completion of the reaction, the product was filtered, concentrated and treated with a solution of sodium carbonate (8.25 g in 100 mL water). The aqueous layer was washed with dichloromethane, acidified and extracted with ethyl acetate (85 mL). The ethyl acetate solution was concentrated to 40 mL and stirred at room temperature for 15 minutes. A fraction of the valsartan precipitated out at this stage to form a suspension. n-Pentane (240 mL) was added to the suspension and was stirred at room temperature. The precipitate was filtered and washed with n-pentane followed by drying under reduced pressure at 50 °C to 55 °C to yield about 6.5 g of valsartan.

Example 4: Isolation of Valsartan 5 g of crude valsartan was dissolved in ethyl acetate (25 mL) by heating. The solution the was cooled to room temperature and stirred for 55 minutes. A fraction of the valsartan precipitated out at this stage to give a suspension. n-pentane (150 mL) was then added to the suspension and was stirred for 30 minutes at room temperature. The precipitate was filtered and washed with n-pentane followed by drying under reduced pressure at 50 °C to 55 °C to yield valsartan.

Yield: 4.6 g Assay: 100.9 % w/w