FIELD OF INVKNTION:

The invention relates to an improved process for the preparation of N-(1-Oxopcntyl)-N-[[2'-(1H-tetrazol-5-yl) [1.1 '-biphenyl]-4-yl]methyl]-L-valine (i.e.Valsartan) Compound of Formula I.

which is used as an antihypertensive drug.

BACKGROUND OF THE INVKNTION:

Valsartan, also known as N-( l-Oxopcntyl)-N-[[2'-(1H-tetrazaol-5-yl) [1,1 '-biphenyl]-4-yl[methyl]-L-valine and is marketed as the free acid under the name DIOVAN. Valsartan is an orally active specific angiotensin II antagonist acting on the AT1 receptor subtype. Valsartan is prescribed for the treatment of hypertension.

US patent No. 5.399,578 and its equivalent European patent No. 0 443 983 B1 disclose valsartan. its pharmaceutically' acceptable salts, pharmaceutical compositions comprising valsartan and their use in treating high blood pressure and cardiac insufficiency. They also disclose a process for the preparation of valsartan. Alternative processes for the preparation of valsartan and its intermediates have been described 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. Bioorganic & Med. Chem. Let.. 4(1) 29-34(1994).

Although many processes have been described for the preparation of valsartan and its intermediates, there remains a need for process that is simple, efficient, cost effective, industrially feasible, and robust for preparing valsartan and its intermediates in high yield and purity.

OBJECTIVE OF THE INVENTION:

An object of the present invention is to provide an improved process for the preparation of valsartan of formula I.

SUMMARY OF THE INVKNTION:

The present invention provide a process for the preparation of valsartan compound of the formula I.

and its salts with a reduced number of synthetic steps, eliminating the need to isolate certain intermediates. The process of the present invention may be practiced on an industrial scale and also may he carried out without sacrificing the overall yield.

In an aspect, the present invention provides processes for the preparation of valsartan, or an alkaline or alkaline earth metal salt thereof, embodiments comprising:

(a) Reacting N-[2'-cyanobiphenyl-4-yl[methyl]-(L)-valine methyl ester hydrochloride with valeryl chloride to give N-[2"-cyanobiphcnyl-4-yl]methyl]-N-valeryl-(L)-valine methyl ester, which is not isolated;

(b) Reacting N-[2"-cyanobiphcnyl-4-yl[methyl]-N-valeryl-(L)-valin] methyl ester with triethylamine hydrochloride and sodium azide to give tctvazole methyl ester, which is not isolated;

(c) Hydrolysing tetrazole methyl ester to give valsartan. which is optionally isolated;

DETAILED DESCRIPTION OF THE INVENTION:

The present invention concerns a novel process for the preparation of compound of formula I which is useful as an anti hypertensive drug. The process provides a novel in situ process for the preparation of compound of formula I.

The goal of the invention under consideration is to design a safe in situ process for the preparation of valsarlan.

This invention also plays more emphasis on synthesis of 5-substitutcd tetrazole compounds.

In this process. N-[2'-cyanobiphcnyl-4-yl[methyl]-(L)-valine methyl ester
hydrochloride with valley chloride to give N-[2'-cyanobiphcnyl-4-yl[methyl]-N-
valeryl-(l,)-valine methyl ester followed by reaction with sodium azidc in presence of
triethyl amine hydrochloride to give tctrazole methyl ester compound followed by
hydrolysis to give valsarlan of formula I.

While the forgoing written description of the invention enables one of ordinary skill to make and use what is considered presently to be the best mode thereof, those of ordinary skill will understand and appreciate the existence of variations, combinations and equivalents of the specific embodiment, method and examples herein. The invention should therefore not be limited by the above described embodiment, method and examples but by all embodiments and method within the scope and spirit of the invention.

EXAMPLE:

Toulene (250mL was placed into flask, sodium carbonate (42.5 g) and water (150ml,) was added followed by addition of N-[2"-cyanobiphcnyl-4-yl]methyl]-(L)-valine methyl ester hydrochloride (50 g). The mixture was cooled to 0-5°C. Valeryl chloride (30 g) was slowly added at the same temperature during 30 min. After completion of addition, the mass was cool to 30°C. the mixture was maintained for about 4 hours. As monitored by T1,C. After the completion of the reaction, aqueous layer was separated and water (150m I,) was added to the organic layer with stirring for about 30 minutes. The organic layer was again separated. 'The organic layer was again separated. To the organic layer, TKA. HC1 (56.8 g) was added followed by addition of sodium azide (26.8 g). The mass was stirred for about 30 minutes and then heated to about 90 °C and maintained for 24 hours. The mass was cool to 30 °C and was washed with water (1 50ml,). Organic layer was added to a pre-cooled solution of sodium hydroxide (22 g) in water (225 ml,) and maintained for 15 hours at 25-30 °C. After the completion of reaction the aqueous layer was separated and washed with toluene (100 ml,). The aqueous layer was extracted with dichloromethane (100mL) and the pi I of the mixture was adjusted to about 6.5 to about 7 using aqueous 1IC1 (100ml,) in water (100 ml,). The organic layer was separated and carbon was added, then the mixture was stirred for about 30 minutes and filtered. The obtained cake was washed with water (50 ml.) cooled to 0-5°C.

To the combined aqueous layer, ethyl acetate (200ml,) was added and the pH was adjusted to about 3 with aqueous HCI. The aqueous layer was separated and extracted with ethyl acetate (50ml,). To the combined organic layer a solution of sodium chloride (10 g) in water (100 ml,) was added. The organic layer was separated and water (200 ml,) was added to it. followed by addition of barium hydroxide (35 g). The mixture was stirred for about 2 hours and then filtered. The filter cake was washed with ethyl acetate (100 ml.). The wet solid was dissolved in ethyl acetate (200 ml,). Water (200ml,) was added to the mixture and stirred for about 30 minutes. The p11 of the mixture was adjusted to 1.5 to 2.0 using a solution of HCI. The mass was stirred for 30 to 45 minutes. The aqueous layer was separated and extracted with ethyl acetate (100 ml,). The combined organic layer was distilled at about 45 °C to obtain residue. Cyelohexane was added slowly to the residue and the mixture was maintained at 25 °C. Stirr for 2 firs at this temperature. The mixture was filtered and was washed with cyelohexane (25 ml,) to yield 21 g of Valsartan.

Chiral Purity: 99.89%

CLAIMS:

1. A process for the preparation of Valsartan which comprises the steps of:

(a) Reacting N-[2-cyanobiphcnyl-4-yl]methyl]-(L)-valine methyl ester hydrochloride with valeryl chloride to give N-[2'-cyanobiphcnyl-4-yl]methyl]-N-valeryl-(L)-valine methyl ester, which is not isolated;

(b) Reacting N-[2'-cyanobiphcnyl-4-yl[methyl]-N-valeryl-(l,)-valine methyl ester with triethylamine hydrochloride and sodium azide to give tetrazole methyl ester, which is not isolated;

(c) Hydrolysing tetrazole methyl ester to give valsartan. which is optionally isolated.

2. The process according to claim 1, where in the steps (a), (b) and (c) arc carried out in single pot.