FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2006
PROVISIONAL SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. -" IMPROVED PROCESS FOR THE PREPARATION OF
VALSARTAN AND ITS INTERMEDIATES"


2. Applicant(s)
(a) NAME: CALYX CHEMICALS AND PHARMACEUTICALS LTD.
(b) NATIONALITY: An Indian Company
(c) ADDRESS: 2. Marwah's Complex, Sakivihar Road, Sakinaka, Andheri (E),
Mumbai-400 072, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.


FIELD OF INVENTION
The present invention relates to an improved process for the preparation of Valsartan, represented structurally by formula I.

Formula I
The present invention further relates to an improved process for the preparation of an intermediate of formula IV and its salts.

Formula IV
The present invention also relates to an improved process for the preparation of Valsartan of formula I from an intermediate of formula VI
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BACKGROUND OF THE INVENTION
N-(l-oxopentyl)-N-[[2'-(lH-tetrazol-5-yl)-[l,r-biphenyl]-4-yl]methyl]-L-vaIine, commonly known as Valsartan (formula I), is a non-peptide angiotensin-II antagonist. Angiotensin is an important participant in the rennin angiotensin-aldosterone system (RAAS) and has a strong influence on blood pressure. Valsartan acts on ATI receptor subtype and is useful in the treatment of hypertension, post myocardial infraction and lung cancer.
A number of methods for the preparation of Valsartan are known in the literature. Valsartan was first disclosed in US patent 5, 399, 578. It was prepared in four step process.
US 5, 399, 578 describes the process for preparation of Valsartan which starts with (i) reductive alkylation of 2-cyanobiphenyl-4'-carboxaldehyde with L-valine benzyl-ester tosylate using sodium cynoborohydride (ii) acylation of the product obtained in step (i) with valeroyl chloride using organic base such as N.N-diisopropyl ethylamine. (iii) The cyano moiety of the product obtained in step (ii) is then converted to tetrazole by reaction with tributyltinazide in xylene at high temperature
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(iv) hydrolytic debenzylation of the product obtained in step (iii) with hydrogen molecule in presence of Pd/C as a catalyst.
The said process is as depicted in Scheme-1

i. Bu3SnN3, xylene, 41 h



C02CH2Ph
N i^ .Me
H2, Pd-C MeOH, rt

Scheme-1
The disadvantages of the process are incomplete reactions, longer time, involves chromatographic purification of intermediates and yield and purity of final product.
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WO 2004101534 discloses the process for preparation of Valsartan by reacting 4-bromomethyl-2'(l-triphenylmethyltetrazo-5-yl)biphenyl with L-valine benzyl ester 4-toluenesulfonate in an organic solvent such as acetonitrile in presence of ethyl diisopropyl amine as a base the product obtained is then reacted with valeroylchloride followed by removal of trityl protecting group
EP 1714963 describes the process for preparation of Valsartan by reacting 4-bromomethyI-2'-cyanobiphenyl with L-valine benzyl ester tosylate in a mixture of organic solvent such as toluene or xylene and water in presence of inorganic base such as potassium carbonate along with potassium iodide and optionally in presence of catalyst such as tetrabutyl ammonium bromide. The major disadvantages of the process is that the reaction takes too long time for completion(25-30h). The product obtained is then acylated with valeroyl chloride in toluene in presence of base such as disopropylamine. The cyano moiety of the product is then converted to tetrazole by reacting it with sodium azide and tributyl tin chloride to obtained benzyl valsartan which is after purification hydrogenated with 5% Pd/C in methanol to get Valsartan.
US20060149079 describes the process for preparing Valsartan by condensing N-[(2'cyanobiphenyl-4-yl)methyl-L-valine methyl ester with valeryl chloride in presence of an inorganic base and solvent such as toluene. The cyano moiety of the product is then converted to tetrazole by reacting it with sodium azide and tributyl tin chloride followed by hydrolysis using inorganic base and suitable solvent.
Organic Process Research and Development, 2007, 11, 892-898 discloses the new production process for Valsartan. The first two steps of the process are mainly modified. The alkylation of L-valine benzyl ester with 4-bromomethyl-2'-cyanobiphenyl is performed under homogeneous condition. The reaction is carried out in xylene in presence of aqueous sodium hydroxide as a base. The product is then
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acylated with valeroyl chloride in xylene in presence of aqueous sodium hydroxide as a base.
All the processes explained above suffer from several drawbacks. All prior art processes use organic solvents in all the four steps of the synthesis. The major problems in most of the cases are incomplete reaction, longer reaction time, presence of impurities/ or starting material/intermediates in the final product. In some cases the reaction time is very large. Therefore there is a need for a novel process towards high yield, more economical and over all environmental friendly process. Since the consumption of organic solvent in all reported processess is very high, there is a need to reduce the consumption of these solvents. In all the prior art the debenzylation step is carried out in organic solvent such as methanol, which carries the undesired and difficult to removal impurities of earlier steps to the final product. Most of the processes use organo tin azides which are toxic and environmentally hazardous chemicals and also need special processes for their disposal.
Hence there is a need to develop an environment friendly and economical process for the preparation of Valsartan of formula I in high yield and purity.
The inventors of the present invention found out an improved process for the preparation of Valsartan of formula I. The process avoids the use of organic solvent in alkylation and debenzylation steps which enhances the purity of the product by reducing undesired impurity. Also, the process of the present invention is less time consuming, cost effective and very environmental friendly.
OBJECT OF THE INVENTION
An object of the present invention is to provide an improved process for the preparation of Valsaratn of formula I.
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Another object of the present invention is to provide a process for the preparation of an intermediate of formula IV and its salts without using any organic solvent.
Another object of the present invention is to provide an improved process for the preparation of Valsartan of formula I from an intermediate of formula VI
Yet another object of the present invention is to provide an improved process for the preparation of an intermediate of formula VI by avoiding use of tin azide.
Yet another object of the present invention is to provide a simple, economical and environmental friendly process in water for the preparation of Valsartan of formula I.
Yet another object of the present invention is to provide an improved process for preparation of Valsartan of formula I in high yield and purity.
SUMMARY OF THE INVENTION

Formula I
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The present invention relates to an improved process for the preparation of Valsartan of formula (I)

The present invention further relates to an improved process for the preparation of an intermediate of formula IV and its salts.
C02Ch2Ph

Formula IV
The present invention also relates to an improved process for the preparation of Valsartan of formula I from an intermediate of formula VI

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of Valsartan of formula I and its intermediates.

According to an aspect of the present invention there is provided an improved process for the preparation of Valsartan of formula I.

Formula I
comprising,
a) reacting 2-cyano-4-bromomethyl biphenyl of formula II with L-valine benzyl ester of formula III in water in the presence of inorganic or organic base to obtain compound of formula IV
b) acylating compound of formula IV with valeroyl chloride in an organic solvent such as toluene in the presence of aqueous inorganic base such as potassium or sodium carbonate or bicarbonate to obtain compound of formula V
c) treating compound of formula V with sodium azide and triethylamine hydrochloride in an organic solvent such as substituted benzenes, ethers or ketones in the presence of triethylamine to obtain compound of formula VI
d) preparing the salt of compound of formula VI
e) hydrogenating the salt of compound of formula VI, obtained in step (d), using H2 in the presence of Pd/C as a catalyst in water to obtain Valsartanan of formula I.
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The process of the present invention for the preparation for Valsartan of formula I is as depicted in Scheme-2

C02H
.N "^ .Me

K2C03, H20
Pd/C

C02CH2Ph
,N L .Me

VI
Scheme -II
In another aspect of the present invention there is provided an improved process for the preparation of an intermediate of formula IV and its salts
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Formula IV
by reacting 2-cyano-4-bromomethyl biphenyl of formula II with L-valine benzyl ester of formula III in water in the presence of inorganic or organic base. The reaction time for completion is only 3-5h.
The alkylation reaction is carried out only in water and without using any organic solvent. All prior art processes report the alkylation reaction in organic solvent. Compound of formula IV is then converted to its salts such as hydrochloride by well known process. L-valine benzyl ester is used in its tosylate form.
In an embodiment of the present invention inorganic base used in the alkylation reaction is selected from alkali carbonates, alkali bicarbonates or alkali hydroxides, preferably form alkali carbonates or alkali bicarbonates such as potassium carbonate, sodium carbonate or sodium bicarbonate, more preferably sodium bicarbonate. Organic bases such as various amines e,g diisopropylethyl amine can also be used in the alkylation reaction in water.
In another embodiment of the present invention the reaction is carried out at temperature ranging from 40 °C to 100 °C, preferably from 50 ° C to 70 ° C, more preferably from 60 ° C to 65 ° C
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In process of the present invention the acylation of compound of formula IV with valeroyl chloride is carried out in organic solvent such as toluene in the presence of inorganic base such as aqueous potassium carbonate solution to obtain compound of formula V.
In an embodiment of the present invention the acylation reaction is carried out at a temperature ranging irom 0 °C to 40 °C, preferably from 10 ° C to 30 ° C, more preferably from 10 ° C to 15 ° C
In an aspect of the present invention the acylation reaction is carried out by maintaining stirring speed. It has been observed by the present inventors that very fast or very slow stirring speed affects the reaction progress. Thus, stirring speed of the reaction is a critical parameter.
According to another aspect of the present invention there is provided the process for the preparation of compound of formula VI by converting cyano moiety of compound of formula V to tetrazole moiety of compound of formula VI. Compound of formula V is treated with sodium azide and triethylamine hydrochloride in an organic solvent such as substituted benzenes, ethers or ketones in the presence of triethylamine at 80-83 °C to obtain compound of formula VI.
The said reaction is carried out by using the process as described in our co-pending Indian patent application 1426/MUM/2008 which is incorporated herein by reference.
The organic solvent used in the above reaction is preferably, substituted benzenes which are selected form mono, di or tri-substituted benzenes such as toluene, xylenes or halobenzenes such as chlorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene; more preferably the solvent used in the reaction is toluene.
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In yet another aspect of the present invention there is provided an improved process for the preparation of Valsartan of formula I from intermediate of formula VI.

comprises,
a) preparing the salt of compound of formula VI
b) hydrogenating the salt of compound of formula VI, obtained in step (a), using H2 in the presence of Pd/C as a catalyst in water
The potassium salt of compound of formula VI is prepared by well known process by treating it with aqueous potassium carbonate.
The catalytic hydrogenation of compound of formula VI to Valsartan of formula I is well known in the prior art. However, all prior art processes describe the said reaction in organic solvent such as in methanol and none of the prior art describes the hydrogenation of salt of benzyl valsartan to obtain Valsartan of formula I.
Formation of potassium salt of benzyl valsartan minimizes the undesired impurity of step-c and does not carried over to Valsartan. Thus, it enhances the purity of Valsartan of formula I.
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Thus, the improved process of the present invention avoids the use of organic solvent in alkylation and debenzylation steps. Hence, is cost effective and environmental friendly. It reduces the undesired impurity of step-c and provides Valsartan in high purity and yield.
The details of the invention provided in the following examples are given by the way of illustration only and should not be construed to limit the scope of the present invention.
Example 1
(S)-N-[(2'-cyanobiphenyl -4-yl)methyl]-(L)-valine benzyl ester hydrchloride
(Formula IV)
L-Valine benzyl ester tosylate (139.8g, 0.36mol) was taken in water. Sodium bicarbonate ( 77.5g, 0.9mol) was added into it under stirring at 25°C. The reaction mixture was stirred for 30 min. 4-bromomethyl-2'-cyanobiphenyl(100g, 0.36mol) was added in to the reaction mixture. The reaction mixture was heated at 65°C for 3-4h. This was cooled to room temperature and extracted with minimum volume of toluene. Dil HC1 was added into the toluene solution to make the HC1 salt of (S)-N-[(2'-cyanobiphenyl -4-yl)methyl]-(L)-valine benzyl ester. The white compound was filtered and washed with water. After drying 136.5g (S)-N-[(2'-cyanobiphenyl -4-yl)methyl]-(L)-valine benzyl ester hydrchloride was obtained (0.31 mol, 86% yield and 98% purity by HPLC).
Example 2
(S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-N-valeroyl-(L)-valme benzyl ester
(Formula V)
The HC1 salt of (S)-N-[(2'-cyanobiphenyl -4-yl)methyl]-(L)-valine benzyl ester(127g, 0.29 mol) was treated with potassium carbonate solution to isolate the free amine and was taken in toluene. The toluene solution was cooled to 5°C and potassium
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carbonate solution [81g (0.58 mol) dissolve in 400 ml of water] was added into it under stirring. Valeryl chloride(56.3g, 0.46mol) was then added dropwise into the reaction mixture under stirring at 0-5°C. The temperature of the reaction mass was brought to 15-20°C and the reaction mixture was stirred at this temperature for 2-3h for complete conversion. Additional 100 ml water was added into the reaction mixture and stirr it for another 30 minute. The organic layer was separated out. Toluene layer was washed with 5% NaHC03 solution and dried over anhydrous sodium sulphate. (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-N-valeroyl-(L)-valine benzyl ester present in the solution was having 98% HPLC purity. The dried organic layer was used as such for the tetrazole formation.
Example 3
(S)-N-(l-benzyloxycarbonyl-2-methyl-prop-l-yl)-N-[2,-(lH-tetrazoI-5-yl)-biphenyl-4-ylmethyl]-amine (Formula VI)
The toluene layer of (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-N-valeroyl-(L)-valine benzyl ester was taken in a flask and sodium azide(123.4g, 1.89 mol), triethylamine Hydrochloride(259.3g, 1.89 mol) was added to it with stirring at 25-30°C. Triethylamine (28.1 ml) in toluene was then added to the reaction mixture and heated to 80°C. The heating was maintained for 50-52h with monitoring by tie. The reaction mixture was cooled to 25-30°C. Sodium nitrite solition (131g, 1.89 mol) was added into it very slowly at 0-5°C to quench the excess of sodium azide present in the reaction mixture. It was then acidified with dil HCI at 0-5°C. Organic layer was separated out and the aqueous layer was extracted with toluene. The organic layer was combined and washed with water and dried over anhydrous sodium sulphate. This was concentrated under vacuum to obtained a yellow colored sticky material. The compound was further purified by dissolving in K2CO3 solution and extracted the undesired compound with diisopropyl ether. The alkaline solution at this stage can be taken as such for hydrogenation or (S)-N-(l-benzyloxycarbonyl-2-methyl-prop-l-yl)-N-[2'-(l H-tetrazoI-5-yI)-biphenyl-4-yl-methyl]-amine[benzyl valsartan] can be
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isolated by neutralising with dil HCl acid followed by extraction with ethylacetate from the reaction mixture.
Example 4
(S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yI)-biphenyl-4-yImethyl]-amine (Valsartan)
The potassium salt of (S)-N-(l-benzyloxycarbonyl-2-methyl-prop-l-yl)-N-[2'-(lH-tetrazol-5-yl)-biphenyI-4-yl-methyl]-amine[benzyl valsartan] (lOg, 0.019 mol) was taken in water and hydrogenated in presence of H2 and 0.5g(5% loading) of 10% Pd/C at room temperature under 1.5 kg pressure. The reaction mixture was stirred for 4h at this temperature. The catalyst is filtered and the aqueous solution is partioned with dichloromethane and then acidified with dil HCl to obtain the product. This was filterd and suck dried to obtain crude valsartan(7.5g, 89% yield, HPLC purity: 97%). On recrystalisation in ethyl acetate valsartan was obtained with purity more than 99.7%.
Dated this 16™ day of February 2009

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