FIELD OF INVENTION

The present invention relates to an improved process for the preparation of valsartan formula 1 and its pharmaceutically acceptable salts.

INTRODUCTION OF INVENTION

Valsartan has the chemical names: (S)-N-( 1 -carboxy-2-methyl prop-l-yl)-N- pentanoyl- N-[2"-1H-tetra/ol-5-yl)biphcnyl-4-ylmcthyl]-amine; or N-(1-Oxopentyl)-N-[[T-(1H- tetrazol-5-yl)] 1 ,r-biphenyl[-4-yl]methyl]-L-valine and is structurally represented by Formula I.

Valsartan is marked as the free acid under the name DIOVAN. Valsartan is non-peptide and orally active specific angiotensin II antagonist acting on the ATI receptor subtype. Valsartan is prescribed for the treatment of hypertension.

U.S. 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. US '578 disclosed a process for the preparation of valsartan, which can be depicted by Scheme 1.

Briefly, the process for the preparation of valsartan comprises of the condensation of N- [(2'-cyanobiphcnyl-4-yl)methyl]-(L)-valine methyl ester of Formula II with valeryl chloridc of Formula III in the presence of diisopropyl amine and dichloromethane, followed by Hash chromatography, to give the compound N-[(2'-cyanobiphenyl-4- yl)methyl]-N-valcryl-(L)-valinc methyl ester of Formula IV. The compound of Formula IV on tetrazole formation using tributyltin azide and subsequent hydrolysis using sodium hydroxide, followed by Hash chromatography, purification gives valsartan of Formula I.

The aforementioned process uses diisopropyl cthylamine in the process for the preparation of the compound of Formula IV, in which process the reaction is incomplete due to presence of moisture, affecting the quality of the product, leading to a lower yield and requiring Hash chromatography for purification. Conversion of the compound of
Formula IV to valsartan also involves flash chromatography, which makes the process difficult to operate on industrial scale.

Alternative processes for the preparation of valsartan and its intermediates have been described in various 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, WO 2004/026847, Bioorganic & Med. Chcm.Lct., 4(1) 29-34 (1994).

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

SUMMARY OF THE INVENTION

The present invention relates to an improved process for the preparation of valsartan of Formula I, and pharmaceutically acceptable salts thereof, one embodiment of the process comprising the steps of:

a) Condensation of N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester compound of Formula II or its hydrochloride salt with the valeryl chloride compound of Formula III in the presence of an organic base and a suitable solvent to give the (N-[(2'-cyanobiphcnyl-4-yl) methyl ]-N-valeryl-(L)-valine methyl ester compound of Formula IV,

b) Tetrazole formation of (N-[(2'-cyanobiphenyl-4-yl) methyl]-N-valeryl-(L)-valine methyl ester compound of Formula IV in the presence of suitable reagents and suitable solvents to provide an intermediate compound of Formula V,

c) I Iydrolysis of the compound of Formula V using a suitable base in the presence of a suitable solvent to yield valsartan, and

d) Optionally, rccrystallisation of the valsartan of step (c) in a suitable solvent(s) to provide the purified valsartan of Formula I.

An aspect of the invention comprises a process for preparing valsartan, comprising condensing N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester, or a salt thereof, with valeryl chloride in the presence of an organic base to form N-[(2'-cyanobiphenyl-4- yl)methyl ]-N-valeryl-(L)-valine methyl ester.

A further aspect of the invention comprises a process for preparing valsartan, comprising hydrolyzing a compound having the Formula V

DETAILED DESCRIPTION

The present invention relates to an improved process for the preparation of valsartan of Formula I, and pharmaceutically acceptable salts thereof, comprising the steps of:

a) Condensation of N-|(2'-cyanobiphcnyl-4-yl)methyl]-(L)-valine methyl ester compound of Formula II or a salt thereof

with the valeryl chloride compound of Formula III

in the presence of an organic base and a suitable solvent to provide (N-[(2'- cyanobiphenyl-4-yl)-methyl]-N-valeryl-(L)-valine methyl ester of Formula IV,

b) Tetrazolc formation of the N-[(2'-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine methyl ester compound of formula IV in the presence of suitable reagents and suitable solvents, to give an intermediate compound of Formula V,

c) Hydrolysis of the intermediate compound of Formula V using a suitable base in the presence of a suitable solvent to provide valsartan of Formula I, and

d) Optionally, reerystallization of crude valsartan in a suitable solvent(s) to give purified valsartan of Formula I.

Formula I

Step a) involves condensation of N-[(2'-cyanobiphenyl-4-yl)-methyl]-(L)-valine methyl ester or a salt, such as its hydrochloride salt, with valeryl chloride in the presence of an organic base and a suitable solvent to give (N-[(2'-cyanobiphenyl-4-yl)methyl]-N- valeryl-(L)-valinemethylester.

Suitable organic bases that can be used in step a) include but are not limited to: unsubstituted or substituted pyridines, anilines, napthalenene amines, tri C1-C7- alkylation’s, basic hetcrocycles or tctra C1-C7-alkyl ammonium hydroxides, tributylamines or N-methyl morpholine, tri-propylamine or N-methyl piperidine, dimethylaniline or dimethylaminonapthalinc, a lutidine, a collidine or benzyltrimethyl ammonium hydroxide. A preferred base is tributylamine. Suitable solvents that can be used include but arc 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 acetate, n-butyl acetate, and the like; nitrites such as acetonitrile, propionitrile and the like; hydrocarbons such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethanc, chloroform and the like; aprotic polar solvents such as N,N- dimcthylformamidc (DMF), dimcthylsulfoxidc (DMSO), N,N-dimethylacetamide (DMA) and the like; and water; or mixtures thereof in various proportions.

Step b) involves tetrazolc formation of the compound of Formula IV in the presence of a suitable tetrazolc forming reagents and in presence of suitable solvent to give an intermediate compound of Formula V.

Suitable tetrazole formation reagents include but are not limited to tributyltin azide and the like, which may be prepared insitu by the reaction of tributyltin chloride and sodium azide.

Suitable solvents that can be used in the tetrazole formation reaction include any solvent or mixture of solvents. I Examples include, without limitation thereto ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acctatc, isopropyl acetate, n-butyl acetate, and the like; halogenated hydrocarbons such as dichloromethanc, chloroform and the like; and aromatic hydrocarbons such as benzene, toluene, xylene and the like.

The intermediate tetrazole compound of Formula V thus formed may or may not be isolated and can be converted into corresponding acid in step c).

Step c) involves hydrolyzing the intermediate compound of Formula V using a suitable base in presence of a suitable solvent to provide crude valsartan of Formula I.

Alternatively, these bases can be used as their solutions in suitable solvents.
Suitable solvents that can be used in the hydrolysis of the tetrazole intermediate compound include any solvent or mixture of solvents in which the required components arc soluble. Examples include alcohols such as methanol, ethanol, propanol and the like; kctonic solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and the like; halogenated solvents such as, dichloromethane, chloroform and the like; aromatic hydrocarbons such as benzene, toluene, xylene and water.

Step d) involves crystallization by dissolving crude valsartan in a suitable solvent to form a clear solution and then cooling to give a pure valsartan compound of Formula I. For obtaining high product yield, the solute concentration should be high, and frequently elevated temperatures will be required to dissolve sufficient solute.

Suitable solvents that can be used in step d) include any solvent or mixture of solvents in which the required components are soluble. Examples include without limitation: ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as methyl acetate, ethyl acctatc, n-propyl acetate, isopropyl acetate, n-butyl acetate, and the like; halogenated solvents such as, dichloromethane, chloroform and the like; nitriles such as acctonitrile, propionitrile and the like;

In one embodiment, clear solution thus obtained during the process can optionally be treated with activated charcoal or any other adsorbent material to improve the color of the compound.

Isolation of the solid can be carried out by using conventional techniques such as centrifugation, decantation, gravity filtration, vacuum filtration, or other techniques known in the art for the separation of solids.

A solid product can be dried using any technique, such as for example fluidized bed drying, aerial drying, oven drying, or other techniques known in the art. Drying can be conducted at temperatures of about 20-100 °C or about 60-70 °C with or without an application of vacuum. It is also conceived that the drying could be carried out under an inert atmosphere, if desired.

Valsartan prepared according to the process of the present invention can be converted into its pharmaceutically acceptable salts by using methods such as those described in U.S. Patent Application Publication No. 2005/0101652. The process of the present invention is improved, cost-effective, coco-friendly and reproducible on an industrial scale.

Certain aspects and embodiments of the processes described herein are further described in the following examples. These examples arc provided solely for the purpose of illustrating certain aspects and embodiments of the invention and therefore should not be construed as limiting the scope of the invention. Purity information in the examples was determined using high performance liquid chromatography ("HPLC") analysis.

EXAMPLE-1:

Methanol (300 ml,) was placed into a flask; L-valine (100 g) was added .The mixture was cooled to 0-5°C. Addition of thionyl chloride (152 g) was slowly at the same temperature during 30 min. After completion of addition the mass was allowed to 45°C, the mixture was maintained for about 12 hours. Temperature was increased to 65°C and the mixture was maintained for about 2 hours Reaction completion was determined using TLC. After the completion of the reaction, organic layer evaporated completely using vacuum. I Dimethyl forearmed (250 mL), 4'-(bromo methyl) biphenyl-2-carbonitrile (200 g) and sodium bicarbonate (270 g) was added. The mass was stirred for about 2-4 hours at about 60 C. Reaction completion was determined using thin layer chromatography and, after the reaction completed, the mass was allowed to cool to 30°C and added water (1800 mL). Addition of hydrochloric acid (250 mL) was slowly at the same temperature during 60 min. and then the mixture was stirred for about 10 hours and filtered. The filter cake was washed with water (100 mL). The wet solid and ethyl acetate (450 mL) was placed into a flask, the mixture was stirred for reflux for 1 hour then cooled to room temperature and filtered. The filter cake was washed with ethyl acetate (100 mL) and dried to get 200 g of (S)-Methyl 2-((2'-cyanobiphenyl-4-yl)methylamino)-3-methylbutanoate hydrochloride. IIPLC purity: 99.52%.

EXAMPLE-2:

Xylene (600 mL) was placed into a flask, tri-n-butyl amine (188.7 g) followed by addition of (S)-Methyl 2-((2'-cyanobiphcnyl-4-yl) methylamino)-3-methylbutanoate hydrochloride (100 g). The mixture was cooled to 0-5°C. Valeryl chloride (54 g) was slowly added at the same temperature during 30 min. After completion of addition the mass was allowed to 30 C, the mixture was maintained for about 4 hours. Reaction completion was determined using TLC. After the completion of the reaction, water (300 ml,) was added to the organic layer with stirring for about 30 minutes. The organic layer was separated and washed with 5% sodium bicarbonate solution (600 mL), evaporate solvent completely under vacuum to get (S)-Methyl 2-(N-((2'-(lH-tetrazol-5-yl)biphenyl- 4-yl)methyl)pcntanamido)-3-mcthylbutanoatc as residue (110 g).HPLC purity: 99.12%.

EXAMPLE-3:

Sodium azide (40 g), tri-n-butyltinehloride (200 g) and xylene (500 mL) were placed in a RBI'. Added (S)-Methyl 2-(N-((2'-(l I I-tetrazol-5-yl) biphenyl-4-yl) methyl) pentanamido)-3-mcthylbutanoatc (110 g) and maintained for 24 hours at reflux. Reaction completion was determined using thin layer chromatography, after the reaction completed, the mass was allowed to cool to 30°C. Organic layer was added to a pre- cooled solution of sodium hydroxide (60 g) in water (240 mL) and maintained for 30 hours at 10-15°C. Reaction completion was determined using TLC and, after the reaction completed. The aqueous layer was separated and the aqueous layer was placed into a flask, dichloromethane (400 mL) was added, and the pH of the mixture was adjusted to about 6.5 to about 7 using a solution of I1CI (70 mL) in water (70 mL). The organic layer was separated and carbon was added to the aqueous layer, then the mixture was stirred for about 30 minutes and filtered. The filter cake was washed with water (50 mL) cooled to 0-5°C. To the combined aqueous layer, ethyl acetate (400 mL) was added and the pH was adjusted to about 3 with a solution of MCI (100 mL) in water (100 mL). The aqueous layer was separated and extracted with ethyl acetate (200 mL). To the combined organic layer was added a solution sodium chloride (60 g) in water (600 mL) was added. The organic layer was separated and water (200 mL) was added to it, the combined organic layer was distilled at about 45°C and a vacuum. Fresh ethyl acetate (450 mL) was added to the distillation residue and the mixture cooled to about 25°C under stirring for about 2 hours. The mixture was further maintained at 0-5°C for about 4 hours and was filtered and washed with ethyl acetate (100 mL) to yield 75 g of Valsartan.

HPLC purity: 99.85%.

Chiral purity: 99.80%

CLAIMS

We claim:

1. A process for preparing valsartan, comprising condensing N-[(2'-cyanobiphenyl- 4-yl)methyl ]-(L)-valance methyl ester, or a salt thereof, with valeryl chloride in the presence of a reaction medium consisting essentially of an organic base and at least one solvent, to form N-|(2'-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine methyl ester.

2. The process of claim 1, wherein an organic base comprises unsubstituted or substituted pyridines, anilines, naphthalene amines, tri C1 -C7-alkylamines, basic hctcrocycles or tetra Cl-C7-alkyl ammonium hydroxides, tributylamines or N- methyl morphemic, tri-propylamine or N-methyl piperidine, dimethylaniline or dimethylaminonapthaline, a lutidinc, collidine or benzyltrimethylammonium hydroxide more preferably tributyl amine..

3. The process of claim 1, further comprising reacting N-[(2'-cyanobiphenyl-4- yl)methyl ]-(L)-valinc methyl ester with tetrazole forming reagent, to form a compound having the formula.

4. The process of claim 3, wherein a tetrazole forming reagent comprises tributyltin azide.

5. The process of claim 4, further comprising hydrolyzing a compound having the formula V to form valsartan followed by purification.

6. The process of claim 5, wherein hydrolyzing comprises reacting with a base.

7. The process of claim 6, wherein hydrolyzing comprises reacting with at least one alkali metal hydroxide, carbonate, or bicarbonate.

8. The process of claim 5, further comprising purifying valsartan by crystallization from a ketone, ester, halogenated solvent, or nitrile.

9. The process of claim 1, wherein a solvent comprises a ketone, an ester, a nitrile, a hydrocarbon, a halogenated hydrocarbon, an aprotic polar solvent, water, or a mixture of two or more thereof.

10. The process of claim 1, wherein a solvent comprises toluene, a xylene, or a mixture thereof.