Title of Invention	AN IMPROVED PROCESS FOR THE SYNHTESIS OF VALSARTAN OF HIGH ENANTIOMERIC PURITY
Abstract	A process for the preparation of valsartan of formula (I) of at least 98% enantiomeric purity comprising the steps (a) preparing a novel oxalate salt of the formula (Ila), (b) converting the compound of formula (Ila) to valsartan of formula (I), and (c) isolating valsartan of formula (I) in an amorphous form.

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COMH£TE AFTER PROVISIONAL '1 0 OCT 2005 FORM2 THE PATENTS ACT, 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10; rule 13) Title of the invention. - AN IMPROVED PROCESS FOR THE SYNHTESIS OF VALSARTAN OF HIGH ENANTIOMERIC PURITY 2. Applicant(s) (a) NAME : (b) NATIONALITY : (c) ADDRESS : LUPIN LIMITED An Indian company 159, CST Road, Kalina, Santacruz (East), Mumbai - 400 098, Maharashtra, India, 3. PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it is to be performed: FIELD OF THE INVENTION The present invention relates to an improved process for the synthesis of Valsartan of high enantiomeric purity. The invention further relates to an oxalate salt of formula Ha which is an intermediate in the production of valsartan BACKGROUND OF THE INVENTION Valsartan of formula (I), chemically known as (S)-N- (l-carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N- [2'-(lH-tetrazol-5-yl)-biphenyl-4-yl-methyl]amine, is an angiotensin receptor antagonist and is useful as an anti-hypertensive agent. (I) US Patent No. 5,399,578 covers Valsartan and discloses a process for its preparation. According to the process described in US'578, Valsartan of formula (I) is prepared by acylating compound of formula (II), (ID with valeryl chloride to give compound of formula (III), (III) subsequent removal of the trityl group using hydrochloric acid, followed by deprotection of benzyloxy group by catalytic hydrogenation with Pd/C in methanol or dioxane. Further, Valsartan is obtained as colorless crystals from diisopropyl ether. The trityl group is removed by treating with IN hydrochloric acid in dioxane, followed by the work up procedure involving, concentrating the reaction mass and rendering it alkaline by the addition of 2N KOH and then extracting the product with ethyl acetate after acidification. It has been found that removal of trityl group under these conditions described in example 55 of US'578 leads to racemization of the product leading to the formation of the undesired (R) isomer of Valsartan up to 1 %, beyond US Pharmacopeia limits, thereby rendering to another purification step which entails in increasing the cost of production. Example 55 of US'578 patent discloses the use of intermediate (II) in its crude form. This example refers to Example 57a for the preparation of intermediate (II) which yields the target compound as oily mass. Thus there is need to provide a process for the synthesis of Valsartan in high enantiomeric purity. OBJECTS OF THE INVENTION An object of the present invention is to provide,a process for the synthesis of Valsartan in high enantiomeric purity, and to isolate Valsartan in an amorphous form. Another object of the present invention is to provide an oxalate salt of formula II a, which is a solid intermediate having good handling characteristics. The said intermediate of formula (Ha) is useful for the synthesis of valsartan of high purity. A further object is to provide a process for preparation of novel oxalate salt of formula Ha. SUMMARY OF THE INVENTION According to one aspect of the present invention there is provided an improved process for the preparation of Valsartan of formula (I), which comprises: a) preparing a novel oxalate salt of formula (Ha), b) converting the compound of formula (Ha) to Valsartan of formula (I), c) isolating the Valsartan of formula (I) in an amorphous form. According to another aspect of present invention there is provided an oxalate salt of formula II a COOH I COOH (Ila) According to another aspect of the present invention there is provided a process for preparation of novel oxalate salt of compound of formula (Ila) comprising: (a) condensing L-valine benzyl ester or its acid addition salts of formula (IV) with N-(Triphenylmethyl)-5-(4-bromomethyl)-biphenyl-2-yl-tetrazole of formula (V), (V) (b) treating the reaction mass with a solution of oxalic acid or any hydrates thereof in an organic solvent at elevated temperature, and (c) cooling and isolating the oxalate salt intermediate of formula (Ila). DETAILED DESCRIPTION OF THE INVENTION In a preferred aspect of the present invention, valsartan of formula (I) is prepared from the intermediate (Ila) by a one-pot reaction. The process of the present invention gives the valsartan of formula (I) of high enantiomeric purity, with the (R)-isomer content not more than 0.5% The synthetic route of the present invention for formation of the valsartan of formula I in high enantiomeric purity is given in the scheme 1: In the process of synthesis of valsartan formula (I) as mentioned above, a one-pot synthesis from the intermediate of formula (Ila) is carried out. In the first step of the said one-pot synthesis, the oxalate intermediate of the formula (Ila) is neutralized by addition of a base to a biphasic mixture of water and a water-immiscible organic solvent containing the intermediate of formula (Ila). The reaction is preferably done by stirring the reaction mass for about 0.5 hours to 2 hours, preferably for 1 hour to 2hours, at 20-40°C, more preferably at 25-30°C. Ammonia is the most preferred base used in this step, though other bases like hydroxides, carbonates, bicarbonates, alkoxides and hydrides are not excluded. In a preferred aspect toluene is used as the water-immiscible organic solvent, though other similar solvents comprising from ethylacetate, butylacetate, benzene, dichloromethane, chloroform are used as well. After the completion of the reaction, the toluene extract is separated, washed with water and brine solution (saturated solution of sodium chloride in water). The toluene extract is then cooled to a range of 10-20°C, more preferably to 15-20°C and to the cooled toluene extract N,N-diisopropylethylamine and valeryl chloride is added. After stirring the reaction mass at 25-35°C for about 1 hour to 4 hours, the reaction is quenched by adding water. The toluene extract after separation and washing with sodium bicarbonate solution and water is subjected to concentration. The residue after concentration is then dissolved in an alcohol like isopropanol and cooled to 10-20°C, preferably to 15-20°C. To the cooled isopropanol layer, pH is adjusted to 5.8-6.5, more preferably to 6-6.2 by adding aqueous HC1 and ammonia solution. It has been surprisingly found that by maintaining the pH of the solution so described hereinbefore the racemization of the product can be controlled to limit the formation of (R)-isomer of Valsartan of formula (I) to less than 0.5%, within US Pharmacopeia limits, thereby reducing cost of manufacture vis-a-vis prior art methods. Thus valsartan of formula I with at least 98% enatiomeric purity, preferably not less than 99.5% is obtained. The reaction mass is then clarified by filtration or other usual means and subjected to catalytic hydrogenation for removing the benzyl ester group. In a further aspect of the present invention the Valsartan of formula (I) is isolated in an amorphous form after the deprotection of benzyl ester group by hydrogenation. The reaction mass obtained from hydrogenation is concentrated and dissolved in sodium hydroxide solution and the Valsartan free acid is precipitated by acidification with cone, hydrochloric acid. The precipitate thus obtained is amorphous in nature. Optionally, the precipitate is extracted into dichloromethane and re-precipitated by cooling to afford Valsartan in an amorphous form. The novel oxalate salt intermediate of formula (Ila), is useful for the synthesis of Valsartan of formula (I) of high enantiomeric purity. The oxalate salt of formula (Ila) is characterized by the melting range of 167-169°C. The process for the preparation of the oxalate intermediate of formula (Ila) comprises condensing L-valine benzyl ester p-toluene sulphonic acid salt of the formula (IV) with N-(Triphenylmethyl)-5-(4-bromomethyl)-biphenyl-2-yl-tetrazole of the formula (V) to get N-[2-(l-Triphenylmethyltetrazol-5-yl)biphenyl-4-yl)methyl]-(L) valine benzyl ester followed by the treatment with oxalic acid or the hydrates of oxalic acid in an organic solvent. Preferably such treatment with oxalic acid or the hydrates of oxalic acid is performed by refluxing the reaction mass in acetone, though other solvents are not excluded. The reaction time is generally 0.5hour to 2hours though extendable till 20hours. After completion the reaction mass is cooled to 20-40°C, preferably to 25-30°C, and the residual solid is isolated by usual means, for example, by filtration or centrifugation. In a preferred embodiment, the isolated solid is again refluxed in acetone for about 0.5hour to 2hour, followed by cooling to 20-40°C, preferably to 25-30°C, followed by isolation of the solid. The process is preferably repeated up to three times. The invention is further illustrated by the following non-limiting examples. EXAMPLE 1 Preparation of N-[(2'-(l-Triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl)methyl]-(L)-valine benzyl ester oxalate salt (compound of formula Ila) L-valine benzyl ester p-toluene sulphonate salt (10 g) was condensed with 4-Bromomethyl-2'-(l-triphenylmethyltetrazol-5-yl)biphenyl (14.99 g) using N, N-diisopropylethylamine (8.52 g) as base, in N,N-dimethylformamide (50 ml) at 25 to 30°C for 17 to 20 hrs. The reaction mixture was poured into a mixture of toluene (50 ml) and water (150 ml). The aqueous phase was extracted with toluene (30 ml). The combined toluene layer was washed with water and concentrated to obtain a residue. The residue thus obtained was dissolved in acetone (150 ml) and a solution of oxalic acid dihydrate (3.66 g) in acetone (50 ml) was added, refluxed for 1 h. The reaction mixture was cooled and filtered. The wet solid was again refluxed in acetone (220.5 ml) for 1 hr, cooled and filtered. The solid obtained was dried at 50 to 60°C under vacuum for 8-10 hrs; yield: 16.35 g. Melting point of the product: 167-169°C. IR spectrum (Perkin Elmer 1600 FTIR): about cm"1 3456, 3028, 2978, 2926, 2855, 1962, 1928, 1816, 1737, 1722, 1691, 1625, 1572, 1511, 1490, 1474, 1446, 1359, 1325, 1297, 1253, 1232, 1211, 1232, 1211, 1194, 1162, 1140, 1114, 1084, 1050, 1026, 1002, 971, 944,906761,751,700,675. 'H-NMR spectrum (Brucker DRX-200 MHz) in CDC13 : 0.85 (d), 3.50-3.88 (m), 5.09-5.11 (m), 6.83 (d), 7.01 (s), 7.17-7.42 (m), 7.82 (m). EXAMPLE 2 Preparation of Valsartan of formula (I) N-[(2'-(l-Triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl)methyl]-(L)-valine benzyl ester oxalate salt (10 g) was suspended in a mixture of toluene (30 ml), water (100 ml) and 25% NH3 (6 ml). The biphasic mixture was stirred for 1 h at 25 to 30°C; the toluene layer was separated, washed with water (20 ml) followed by brine (10 ml). The toluene layer was then cooled to 15 to 20°C to which N, N-diisopropylethylamine (3.3 g) followed by Valeryl chloride (2.18 g in 2.2 ml of toluene) were added. The reaction mixture was stirred at 25 to 30°C for 2 to 3 hrs, quenched by adding water. The toluene layer was separated and washed with 2% NaHC03 (10 ml) followed by water. The toluene layer was concentrated at 40 to 50°C to give N-[(2'-(l-Triphenylmethyl-tetrazol-5-yl)-N-valeryl (L)-valine benzyl ester as thick mass. The above thick mass was dissolved in isopropyl alcohol (43 ml), cooled to 15 to 20°C. To the cooled solution was added cone. HC1 (7.2 ml) and stirred for 2 to 4 hrs at 15 to 20°C. The pH of the reaction mixture was adjusted to 6-6.2 with 25% NH3 (8 ml) solution, and filtered through celite. The filtrate was subjected to hydrogenation at 70-80 psi H2 pressure for 1-3 hrs in presence of 10% Pd/C catalyst (7.0 g). The hydrogenation reaction mixture was filtered and concentrated at 40 to 45°C under vacuum. The residue obtained was added to 10% NaOH (13 ml) followed by water (37 ml) at 10 to 15°C. The aqueous layer thus obtained was washed with dichloromethane (2 x 20 ml). The aqueous layer was cooled to 10°C and acidified to pH 1.5-2.0 with cone. HC1 (4.5 ml). The aqueous layer was extracted with dichloromethane (28 ml), the dichloromethane layer was washed with water, dried, cooled to 0-2°C and stirred to obtain the product. Valsartan that was dried at 50 to 60°C under vacuum for 8 to lOhrs. EXAMPLE 3 Preparation of Valsartan of formula (I) N-[(2'-(l-Triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl)methyl]-(L)-valine benzyl ester oxalate salt (10 g) was suspended in a mixture of toluene (30 ml), water (100 ml) and 25% NH3 (6 ml). The biphasic mixture was stirred for 1 h at 25 to 30°C; the toluene layer was separated, washed with water (20 ml) followed by brine (10 ml). The toluene layer was then cooled to 15 to 20°C to which N, N-diisopropylethylamine (3.3 g) followed by Valeryl chloride (2.18 g in 2.2 ml of toluene) were added. The reaction mixture was stirred at 25 to 30°C for 2 to 3 hrs, quenched by adding water. The toluene layer was separated and washed with 2% NaHCCh (10 ml) followed by water. The toluene layer was concentrated at 40 to 50°C to give N-[(2'-(l-Triphenylmethyl-tetrazol-5-yl)-N-valeryl (L)-valine benzyl ester as thick mass. The above thick mass was dissolved in isopropyl alcohol (43 ml), cooled to 15 to 20°C. To the cooled solution was added cone. HCl (7.2 ml) and stirred for 2 to 4 hrs at 15 to 20°C. The pH of the reaction mixture was adjusted to 6-6.2 with 25% NH3 (8 ml) solution, and filtered through celite. The filtrate was subjected to hydrogenation at 70-80 psi H2 pressure for 1-3 hrs in presence of 10% Pd/C catalyst (7.0 g). The hydrogenation reaction mixture was filtered and concentrated at 40 to 45°C under vacuum. The residue obtained was added to 10% NaOH (13 ml) followed by water (37 ml) at 10 to 15°C. The aqueous layer thus obtained was washed with dichloromethane (2 x 20 ml). The aqueous layer was cooled to 10°C and acidified to pH 1.5-2.0 with cone. HCl (4.5 ml), stirred for 10 to 12 hrs to obtain the Valsartan in amorphous form. WE CLAIM: 1. A process for the preparation of valsartan of formula (I) of at least 98% enantiomeric purity comprising the steps (a) preparing a novel oxalate salt of the formula (Ila), (b) converting the compound of formula (Ila) to valsartan of formula (I), and (c) isolating valsartan of formula (I) in an amorphous form. 2. A process of claim 1 where in the step (a) the oxalate salt of the formula (Ila) is prepared by a process comprising the steps (a) condensing L-valine benzyl ester or its acid addition salts thereof of the formula (IV) with N-(Triphenylmethyl)-5-(4-bromomethyl)-biphenyl-2-yl-tetrazole of the formula (V), (b) treating the reaction mass with a solution of oxalic acid or any hydrates thereof in an organic solvent at elevated temperature, and (c) cooling and isolating the oxalate salt intermediate of formula (Ila). 3. A process of claim 1 where in the step (b) the compound of formula (Ila) is converted to valsartan of the formula (I) by a one-pot reaction comprising the steps (a) neutralizing the oxalate salt of formula (Ila) by a base, preferably ammonia, (b) extracting the product in a water immiscible organic solvent, (c) treating the extract with valeryl chloride in presence of a base, (d) treating the reaction mass with hydrochloric acid in isopropanol, (e) hydrogenating the reaction mass in presence of a hydrogenation catalyst, and (f) acidifying the reaction mass after hydrogenation 4. A process as claimed in claim 3 wherein the base for neutralizing the oxalate salt of formula (Ila) is selected from like hydroxides, carbonates, bicarbonates, alkoxides and hydrides, preferably ammonia. 5. A process as claimed in claim 3 wherein the water immiscible organic solvent is selected from toluene, ethylacetate, butylacetate, benzene, dichloromethane, chloroform, preferably toluene. 6. A process of claim 4 wherein at the step (d) g the pH of the reaction mixture is adjusted to 5.8 to 6.5 to control racemization of the final product to limit the formation of (R)-isomer thereby avoiding further purification of the final product. 7. A novel intermediate of the formula (Ila) COOH N'N • I '/ *N COOH N CPh3 (Ila) having melting point of 167-169°C 8. A process for the preparation of a compound of the formula (Ila) comprising the steps (Ila) (a) condensing L-valine benzyl ester or its acid addition salts thereof of the formula (IV) with N-(Triphenylmethyl)-5-(4-bromomethyl)-biphenyl-2-yl-tetrazole of the formula (V), treating the reaction mass with a solution of oxalic acid or any hydrates thereof in an organic solvent at elevated temperature, and (c) cooling and isolating the oxalate salt intermediate of formula (Ha). 9. A process of claim 3 where the step (d) further comprises of adjusting the pH of the reaction mixture to 6-6.5. 10. A process for the preparation of valsartan of formula (I) of at least 98% enantiomeric purity from the compound of the formula (Ha) by a one-pot reaction comprising of (a) neutralizing the oxalate salt of formula (Ha) by a base, preferably ammonia, (b) extracting the product in a water immiscible organic solvent, (c) treating the extract with valeryl chloride in presence of a base, (d) treating the reaction mass with hydrochloric acid in isopropanol, (e) hydrogenating the reaction mass in presence of a hydrogenation catalyst, and (f) acidifying the reaction mass after hydrogenation. 11. A process of claim 10 where the step (d) further comprises of adjusting the pH of the reaction mixture to 6-6.5. Dated this 8th day of October 2005 Dr. Sanchita Ganguli Of S. MAJUMDAR & CO. Applicants' Agent

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