PROCESS FOR THE PREPARATION OF VALSARTAK INTERMEDIATE

FIELD OF THE INVENTION

The present patent application relates to an improved process for the preparation of N-l(2'-cyanobiphenyl-4-yl) methyl]-{L)-valine alkyl ester or a salt thereof, an active intermediate in the preparation of Valsartan.

BACKGROUND OF THE INVENTION

Valsartan is chemically described as (S) N-(l-carboxy-2-methyl-prop-l-yl-N-pentanoyl-N-[[2'-(lH-tetrazol'5-yl)biphenyl-4-yl methyl]--amine and is striacturally represented by Formnla I.

Valsartan is a non-peptide, orally active, specific angiotensin 11 antagonist, useful in the treatment of hypertension and is commercially available in the market under the brand name DIOVAN as 40, 80, 160 and 320 mg oral tablets.

U.S. Pat. No. 5,399,578 discloses valsartan, its pharmaceutically acceptable salts, pharmaceutical compositions comprising valsartan and their use in treating high blood pressure and cardiac insufficiency. It also discloses a process for the preparation of valsartan.

Processes for preparation of valsartan, its pharmaceutically acceptable salts and intermediates have been described in; US 5,965,592, US 5,260,325, US 6,271,375, International Application Publication Nos. WO 02/006253, WO 01/082858, and WO 99/067231; U.S. Patent Application Publication Nos. 2006/0258878 and US 2006/0281801;

Valsartan and its intermediates are required to be prepared in chirally pure form. But they are prone to racemization in extreme reaction conditions. All of the processes hither to known appear to use expensive, hazardous solvents or reagents, resulting lower yields, making the process not suitable for commercial manufacturing.

Therefore there is a need for a process, which is advantageous in preventing racemization, so as to increase the yields of the final product and also to yield an enantiomerically pure form of valsartan and its pharmaceutically acceptable salts and intermediates.

SUMMARY OF THE INVENTION

In one aspect, the present patent application provides a process for the preparation of N-[(2'-cyanobiphenyI-4-yl) methyl]-(L)-valine alkyl ester or a salt thereof that includes:

a) reacting 4-halomethyl-2'-cyanobiphenyl of Formula II with L-valine alkyl ester of Formula III in the presence of an inorganic base and a ketone solvent; where X is CI, Br, 1; and R is C1-C4 alkyl;

b) optionally, converting the obtained N-[(2'-cyanobiphenyl"4-'yl) methylj-(L)-valine alkyl ester of Formula IV in to its acid addition salt by reacting with an acid.

In another aspect the present application provides a process for purification of N-[(2'-cyanobiphenyh4-yl) methyl]-{L)-valine alkyl ester or a salt thereof comprising:

a) providing a mixture of N-[(2'-cyanobiphenyl-4-yl) methyl]-(L)-valine alkyl ester or a salt thereof and an alcohol solvent at a suitable temperature; and

b) recovering the pure N-[{2'-cyanobiphenyl-4-yi) methyl]-{L)-vaiine alkyl
ester or a salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present patent application provides a process for the preparation of N-[(2'-cyanobiphenyl'4-yl) methyl]-(L)-valine alkyl ester or a salt, thereof that includes:

a) reacting 4-halomethyl-2'-cyanobiphenyl of Formula II with L-valine alkyl ester of Formula III in the presence of an inorganic base and a ketone solvent; where X is CI, Br, I; and R is C1-C4 alkyl;

b) optionally, converting the obtained N-[(2'-cyanobiphenyl-4-yI) methyl]-(L)-valine alkyl ester of Formula IV into its acid addition salt by reacting with an acid.

Formula IV

4'haiomethyl-2'-cyanobiphenyl that may be used in the process of step a) includes 4-chloromethyl-2'-cyanobiphenyl, 4-bromomethyl-2'-cyanobiphenyl, 4-iodomethyl-2'-cyanQbiphenyl-, preferably 4-bromomethyl-2'-cyanobiphenyl.

L-valine alkyl ester that may used include C1-C4 alkyl ester such as methyl, ethyl, n-propyl, isopropyl, tert-butyl; preferably methyl ester.

L-valine alkyl ester that may used in the process of step a) is either in the form of salt such as HCl, HBr or in free base form.

Suitable inorganic bases that can be used in step a) include but are not limited to; hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate, and the like; and bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like; or mixtures thereof.

The amount of base that can be used in the reaction can vary depending upon the base used. Suitably, the molar ratio of base to the starting material (L)-valine alkylester of Formula III can range from about 1.5 to 6, or about 2 to 5, or about 3.

Suitable solvents that can be used include but are not limited to: ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl aceiate, n--butyl acetate, and the like;

In one variant, the reaction of step a) may be carried out in the presence of a phase transfer catalyst. Suitable phase transfer catalyst includes but is not limited to tetra butyl ammonium bromide (TBAB), methyltrioctylammonium chloride and the like, Tetra butyl ammonium bromide is preferred.

Suitable temperatures for conducting the reaction can range from about 25°C to about reflux temperature of the solvent used, preferably about 40°C to about 80°C. The reaction can be conducted till the completion of the reaction. Typically the reaction time varies from about 1 hour to about 20 hours or about 8-12 hours.

After completion of the reaction, the reaction mixture may be cooled and the solid materials are removed by filtration. The filtrate may be distilled to remove the solvent and then water is added. The product may be extracted into a suitable organic solvent at a suitable pH such as about 7.5 to about 10 being suitable. Organic layer containing the product may be separated washed with water and proceed to next step directly or it can be distilled to obtain the product as residue.

Suitable solvent that may be useful for extracting the product includes esters such as ethyl acetate, n-propylacetate, isopropyl acetate and the like; hydrocarbon solvents such as toluene, xylene and the like.

Step b) involves converting the obtained N-|(2'-cyanobiphenyl-4-yi) methyl]-(L)'Valine alkyl ester of Formula IV in to its acid addition salt by reacting with an acid.

In one embodiment the organic layer obtained in step a) is reacted directly with acid to form acid addition salt.

In another embodiment the residue obtained in step a) is dissolved in suitable solvent such as water, esters such as ethyl acetate, n-propylacetate, isopropyl acetate and the like; hydrocarbon solvents such as toluene, xylene and the like; and reacted with acid to form acid addition salt.

In yet another embodiment the filtrate obtained after removal of solid is directly reacted with acid optionally in the presence of water to form acid addition salt.

Suitable acids include hydrobromic acid, hydrochloric acid, and organic acids, such as acetic acid, succinic acid, oxalic acid, tartaric acid, formic acid, and maleic acid. Preferable acid is Hydrochloric acid.

The product obtained may be further dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at temperatures of about 35° C to about 70° C with or without vacuum. The drying can be carried out for any desired time periods to achieve the desired product purity, times from about 1 to 20 hours frequently being appropriate.

In one embodiment 4'bromomethyl-2'-cyanobiphenyl is reacted with L-valine methyl ester HCI in the presence of an inorganic base and a ketone solvent.

In another specific embodiment 4-bromomethyl-2'-cyanobiphenyl is reacted with L-valine methyl ester HCl in the presence of sodium carbonate in acetone solvent.

In another aspect the present application provides a process for purification of N-|{2'-cyanobiphenyl-4-yl) methyl]-{L)-valine alkyl ester or a salt thereof comprising:

a) providing a mixture of N-[(2'-cyanobiphenyl-4-yl} methyl]-(L)-valine alkyl ester or a salt thereof and an alcohol solvent at a suitable temperature; and

b) recovering the pure N-[f2'-cyanobiphenyl-4-yl) methylj'(L)-valine alkyl ester or a salt thereof.

In one embodiment, the step of providing a mixture includes mixing N-[(2'-cyanobiphenyh4-yl) methyl]-(L)-valine alkyl ester or a salt thereof with an alcohol solvent.

In another embodiment, the providing step includes mixing free base of N'[(2'-cyanobiphenyl-4-yl) methyl]-(L)-valine alkyl ester in an alcohol solvent, treating the free base solution with an acid to obtain N-[(2'-cyanobiphenyl-4-yl) methyl]-(L)-valine alkyl ester or a salt thereof.

In yet another embodiment, the providing step includes obtaining a reaction mixture in which N-[(2'-cyanobiphenyI-4-yl} methyl]-{L)-valine alkyl ester free base is formed as product in an alcoholic solvent and treating the free base solution with an acid to obtain N-[(2'-cyanobiphenyi-4-yl) rnethyll-(L)-valine alkyl ester or a salt thereof.

The temperatures for providing mixture may range from about 20°C to about 100°C depending on the solvent used. Preferably, purification is carried out at about 60°C to about 80°C, preferably at about 70°C to about 75 °C.

The quantity of solvent used for providing solution depends on the solvent and the temperature opted for the process. The concentration of N-[(2' cyanobiphenyl-4-yl) methyl]-(L)-valine alkyl ester or a salt thereof in the solution may generally range from about 0.1 to about 10 g/ml of the solvent.

The solution of N-[(2'-cyanobiphenyl-4-yl) methyl]-(L)-valine alkyl ester or a salt thereof is optionally treated with activated charcoal for about 10 to 30 minutes. The charcoal along with the undissolved particles may be removed suitably by filtration, centrifugation, decantation, and other techniques. Depending upon the equipment used, concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.

The preferred solvents include CI - C5 alcohols, and mixtures thereof. The particular solvents suitable for the providing step include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol and mixtures thereof. Isopropanol is most preferred

Suitably the reaction solution is cooled to a lower temperature than the mixing temperature to cause precipitation. In another variant, the solution may be concentrated to such an extent where precipitation is occurred it the solution may be concentrated followed by cooling to cause precipitation.

Step b] involves recovering the pure N-[(2'-cyanobiphenyl-4-yl) methylj-(L)-valine alkyl ester or a salt thereof.

The precipitated solid may be isolated by any method including decantation, filtration by gravity or by suction, centrifugation, and the like.

Other techniques for separating the solids from the reaction mixtures are also within the scope of this invention

The process may include further drying of the product obtained with or without vacuum and in presence or absence of inert atmosphere as described previously.

The N-[(2'-cyanobiphenyl-4-yl) methyl]-(L)-valine alkyl ester or a salt thereof obtained by the process of present application may be converted to valsartan or a salt there of by following procedures known in the art such as US2006/0149079 Al.

The process of the present invention is simple and convenient for commercial manufacturing.

Having thus described the invention with reference to particular preferred embodiments and illustrative example, those in the art may appreciate modification 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 for the 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 know to those of ordinary skilled in the art and are described in numerous publications. All references mentioned herein are incorporated in their entirety.
EXAMPLES Example 1: Preparation of N-[(2'-cyanobiphenyl-4-yl) methyl1-(L)-valine methyl ester hydrochloride

25 gm of L'valine methyl ester HCl, 31.25 gm of 4-bromomethyl-2'-cyanobiphenyl, 48 gm of sodium carbonate and 1.5 gm of TBAB were charged in 150 ml of acetone in a flask at room temperature. The reaction mixture was heated to reflux (60-65 °C} and was maintained for about 12 hours at reflux. After completion of the reaction, the reaction mixture was cooled to 30°C. The solid removed by filtration and washed with 15 ml of acetone. The filtrate was distilled completely to remove acetone to obtain 54 gm of residue.

The residue was dissolved in 150 ml of toluene and washed with water (2X100 mlj.The fmal toluene layer pH was adjusted to about 2.0 with 34 % w/w aqueous HCl (15 ml). The reaction mixture was stirred for 30 minutes, filtered the solid and washed with 15 ml of toluene. The wet solid was dried at 50-60°C for about 4 hours to obtain 36.5 gm of the tide compound. Purity by HPLC: 98.5 % w/w
Example 2: Purification of N-[(2'-cyanobiphenyl-4-yl) methyl]-(L)-valine methyl ester hydrochloride

10 gm of dry N-[(2'-cyanobiphenyl-4'yl) methyl]-(L)-valine methyl ester hydrochloride obtained in Example 1 was charged in a flask containing 30 ml of isopropanol. The mixture was heated to reflux and stirred for 30 minutes. The mixture was cooled to about 30°C and stirred for 30 minutes. The solid was filtered and washed with isopropanol (10 ml). The wet solid was dried at 50-60°C for about 4 hours to obtain 8 gm of the title compound Purity by HPLC: 99.8 % w/w
Example 3: Preparation of N-[(2'-cyanobiphenyl-4-yl) methyl]-(L)-valine methyl ester hydrochloride

25 gm of L-valine methyl ester HCl, 31.25 gm of 4-bromomethyh2'-cyanobiphenyl, 50 gm of potassium carbonate and 1.5 gm of TBAB were charged in 150 ml of acetone in a flask at room temperature. The reaction mixture was heated to reflux (60-55 °C) and was maintained for about 12 hours at reflux. After completion of the reaction, the reaction mixture was cooled to SO°C. The solid removed by filtration and washed with 15 ml of acetone. The filtrate was distilled completely to remove acetone to obtain 54 gm of residue.

The residue was dissolved in 150 ml of toluene and washed with water (2X100 ml). The final toluene layer pH was adjusted to about 2.0 with 34 % w/w aqueous HCl (15 ml). The reaction mixture was stirred for 30 minutes, filtered the solid and washed with 15 ml of toluene. The wet solid was dried at 50-60 °C for about 4 hours to obtain 34 gm of the title compound.
Example 4: Preparation of N-[(2'-cyanobiphenyl-4-yl) methyl]-(L)-valine methyl ester hydrochloride

25 gm of L-valine methyl ester HCl, 31.25 gm of 4-bromomethyl-2'-cyanobiphenyl and 48 gm of sodium carbonate were charged in 150 ml of acetone in a flask at room temperature. The reaction mixture was heated to reflux (60-65 °C) and was maintained for about 12 hours at reflux. After completion of the reaction, the reaction mixture was cooled to SO°C. The solid removed by filtration and washed with 15 ml of acetone. The filtrate was distilled completely to remove acetone to obtain 52 gm of residue.

The residue was dissolved in 150 ml of toluene and washed with water (2X100 ml).The final toluene layer pH was adjusted to about 2.0 with 34 % w/w aqueous HCl (20 ml). The reaction mixture was stirred for 30 minutes, filtered the solid and washed with 20 ml of toluene. The wet solid was dried at 50-50 °C for about 4 hours to obtain 36 gm of the title compound.
ETcample 5: Preparation of N-[(2'-cyanobiphenyl-4-yl) methyl]-(L)-valine methyl ester hydrochloride

25 gm of L-valine methyl ester HCl, 31.25 gm of 4-bromoniethyl-2'-cyanobiphenyl and 48 gm of sodium carbonate were charged in 150 ml of ethylacetate in a flask at room temperature. The reaction mixture was heated to reflux (60-65 °C) and was maintained for about 12 hours at reflux. After completion of the reaction, the reaction mixture was cooled to 30°C. The solid removed by filtration and washed with 15 ml of ethylacetate and water (IxlOOml). The filtrate was distilled completely to remove ethylacetate to obtain 39 gm of residue.

The residue was dissolved in 117 ml of toluene .The final toluene layer pH was adjusted to about 2.0 with 34 % w/w aqueous HCl (17 ml). The reaction mixture was stirred for 30 minutes, filtered the solid and washed with 20 ml of toluene. The wet solid was dried at 50-60 °C for about 4 hours to obtain 37 gm of the title compound.

Claims:
1). A process for the preparation of N-[{2'-cyanobiphenyl-4-yl) methyl]-(L)-valine alkyl ester or a salt thereof comprising the steps of:
a)reacting 4'halomethyl-2'-cyanobiphenyl of Formula II with L-Valine alkyl ester of Formula III in the presence of an inorganic base and a ketone solvent;

where X is CI, Br, I; and R is C1-C4 alkyl;

b)converting the obtained N-[{2'-cyanobiphenyl-4-yl) methyl]-(L)-Valine alkyl ester of Formula IV into its acid addition salt by reacting with an acid.

Formula IV 2). The process of claim 1, wherein 4-halomethyl-2'-cyanobiphenyl of formula II is selected from 4-chloromethyl-2'-cyanobiphenyl, 4-bromomethy]-2'-cyanobiphenyl, 4-iodomethyl-2'-cyanobiphenyI.

3). The process of claim 1, wherein L-valine alkyl ester is in the form of free base or its acid addition salts thereof.

4). The process of claim 1, wherein the base is inorganic base selected from hydroxides of alkali metals, carbonates of alkali metals and bicarbonates of alkali metals.

5). The process of claim 1, wherein the reaction of step a) is carried out in a solvent selected from acetone, ethyl methyl ketone, methyl isoljutyl ketone, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate and mixtures thereof.

6). The process of claim 1, wherein the ketone solvent is acetone.

7). The process of claim 1, wherein the reaction of step a) is carried in presence of phase transfer catalyst selected from tetra butyl ammonium bromide (TBAB), methyltrioctylammonium chloride.

8).The process of claim 1, wherein the mole ratio of base added to the L-Valine methyl ester is from about 1:1 to 1:6.

9).The process of claim 1, wherein the reaction of step b) acid addition salt is selected from acids HCl, HBr or from organic acids selected form oxalic acid, acetic acid, succinic acid, tartaric acid, formic acid, and maleic acid.
10). A process for the purification of N-[[2'-cyanobiphenyl-4-yl] methyl]-(L)- valine alkyl ester or a salt thereof comprising the steps of

a)providing a mixture of N-[(2'-cyanobiphenyl-4-yl) methyl]-fL)-valine alkyl ester or a salt thereof and an alcohol solvent at a suitable temperature; and

b)recovering the pure N-[(2'-cyanobiphenyl-4-yl) methyl]-(L)-valine alky]ester or a salt thereof.

11). The process of claim 11,wherein the mixture includes N-[(2'- cyanobiphenyl-4-yl) methyl]-(L)-valine alkyl ester or a salt thereof and an alcohol solvent.

12). The process of claim 11, wherein the alcohol solvents are selected from CI-C5 alcohols or the mixtures thereof.

13). The process of claim 11, wherein the alcoholic solvent is methanol.

14). The process of claim 11, wherein the suitable temperature is from 40°C to 100°C.

15). A method of using N-[(2'-cyanobiphenyl-4-yl) methyl]-(L)-valine alkyl ester or a salt thereof in the synthesis of active pharmaceutical ingredients including
Valsartan.