FORM-2
The Patent Act, 1970
(39 of 1970)
Complete Specification
(Section 10; Rule 13)
Title: - Process for the preparation of valsartan and its intermediates.
Address of the Applicant
M. M. V. Ramana, Nitesh Sudhakar Chaudhari and S.V. Rathod.
Department of Chemistry, University of Mumbai, Vidyanagari, Santacruz (East), Mumbai: 400098.
The following specification describes the invention, and the manner in which it is to be performed

Title: Process for the preparation of valsartan and its intermediates. Field of invention:
The present invention relates to various aspects of process for the preparation of leading angiotensin receptor blocker (ARB; also called angiotensin II receptor antagonist or AT1 receptor antagonist), its intermediates and process steps of a known pharmaceutical agent, valsartan in substantially pure enantiomeric form.
Valsartan is used for the treatment of hypertension and related diseases and conditions. Prior Art:
Valsartan, also known as (s)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2-(lH-tetrazoI-5-yl)biphenyl-4-ylrnethyl]-arnine, has the following structure:

Preparation of Valsartan and/or its intermediates are disclosed in various references, including: U.S. Pat. Nos. 281,801; 100,443; 6,271,375; 5,965,592; 5,399,578; 5,260,325; WO 2007/005967; WO 2005/102987; WO 01/082858; WO 97/30036; EP 1777224
These processes leave space for improvement of aspects such as avoiding utilization of metals like Mg, Ni, Pd, etc. and toxic metals like tin, use of large protective groups such as trityl group for the tetrazole ring and benzyl group for the carboxylic acid of the valine moiety, which on removal of protecting groups, results in a process of low atomic efficiency. This increases the number of synthesis steps in the process and produces considerable amount of residual products. For N-acylation conventional processes generally use acyl chloride or acid and thionyl chloride, phosphorous trichloride, phosphorous pentachloride, which are corrosive and environment non-friendly chemicals. Some of the processes lead to racemization and subsequent separation of enatiomers is needed.
Thus there is a need for simple, safe, economical, environment friendly and high-yield process for the preparation of valsartan,in substantially pure enantiomeric form.
Description of the invention:
The objective of the present invention is to synthesise compound of formula (I) that avoids (1) use of heavy metals such as Pt, Pd, etc costly reagents and reactants, (2) use of boronic acid derivatives, (3) corrosive chemicals such as acid chloride, thionyl chloride, phosphorous

trichloride, phosphorous pentachloride, etc., (4) use of toxic substances such as organotin compounds, (5) use of compounds that leave metal residue in the products.
The process should be (1) high-yield process, (2) economically attractive by minimizing number of steps, (3) afford enantiometrically pure products, (4) capable of being carried out on a large scale.without racemisation of products.
The present invention is successful in attaining the above objectives.
In the first step, 2-cyano-4'-methylbiphenyl (II) is synthesised from 2-aminobenzonitrile and alkyl nitrite preferably t-butyl nitrite by coupling with toluene.

2-cyano-4'-methylbiphenyl (II) is a very important intermediate in the synthesis of Valsartan
(I) In the second step of this invention is to provide a process for preparation of 4'-
bromomethyI-2-cyanobiphenyI (III) from 2-cyano-4'-methyIbiphenyl (II). This is carried out
with 2-cyano-4'-methy1biphenyl (II) and N-bromosuccinimide.

4'-bromomethyl-2-cyanobiphenyl (III) is also a very important intermediate in the synthesis of Valsartan (I).
A third step of the invention is the synthesis of N-[(2'-cyanobiphenyl-4-yl)-methyl]-(s)-valine methyl ester (IV). This is synthesised by refluxing 4'-bromomethyl-2-cyanobiphenyl (III) and (s)-valine methyl ester in acetonitrile.


A fourth step of the invention is the synthesis of N-pentanoyI-N-[(2-cyanobiphenyl-4-yl)-methyl]-(s)-valine methyl ester (V). This is synthesised from N-[(2-cyanobiphenyl-4-yl)-methyl]-(s)-valine methyl ester (IV) using pentanoic acid in presence of catalytic amount of CoCI2.6H2O.

A fifth step of the invention is the synthesis of N-pentanoyl-N-[(2-(lH-tetrazol-5-yl)-biphenyl-4-yI)-methyI]-(s)-valine methyl ester (VI) by reacting N-pentanoyl-N-[(2-cyanobiphenyl-4-yl)-methyl]-(s)-valine methyl ester (V) with sodium azide and triethyi amine hydrochloride.

Finally, Valsartan (I) is synthesised by alkaline hydrolysis of N-pentanoyl-N-[(2-(lH-tetrazol-5-yl)-biphenyl-4-yl)-methyl]-(s)-valine methyl ester (VII).
In this invention Valsartan is prepared by simple, safe, environmentally friendly process, starting from simple and commercially available, inexpensive chemicals and in good yield with high optical purity. Thus process is applicable also on a large scale. This process avoids use of large protecting groups, such as trityl group for tetrazole, acyl chlorides and related corrosive chemicals, toxic chemicals such as boronic acid derivatives and organotin compounds, heavy metals and costly catalyst like Pd compounds. This process of preparing Valsartan (I) is economically more attractive as it is achieved in less number of steps.
Some aspects of the synthesis of Valsartan (I) and its intermediates are illustrated in examples.
Examples:
Example 1

Synthesis of 2-cyano-4'-methylbiphenyl (II)
2-aminobenzonitrile (1.534 g, 0.013 mol) and t-butylnitrite (1.612 g, 0.0156 mol) was taken in a 50 ml round bottom flask and stirred at 25° C for 20 minutes. Then toluene (10 ml) was added. Reaction mixture was refluxed for 2 hours at 120° C. After this period solvent was recovered by vacuum distillation to a yield coloured mass. This coloured mass was purified by column chromatography using silica gel (100 g) adsorbent. Elution with pet.ether: chloroform (90:10) followed by recovery of solvent gave unreacted toluene further elution and recovery of solvent afforded colourless crystals of 2-cyano-4'-methylbiphenyl (II) (1.0 g, Yield= 40%), m.p. 51°C.
IR Spectrum (KBr): 3245, 3065,3021, 2901,2216, 1603,1560, 1501,850,755.
1H-NMR, (CDCI3), (300 MHz), δ (ppm): 2.447 (s, 3 H), 7.408-7.536 (m, 4H), 7.615-7.801 (m, 4H).
13C-NMR, (CDCI3), (75 MHz), δ (ppm): 22.141, 112.111,119.961,128.462, 128.619, 130.082,
134.007, 135.114, 135.124, 136.976, 137.243, 146.482.
MS(m/z): 193 (M+), Elemental analysis:
Elements %C %H %N
Found 86.87 5.61 7.09
Calculated for C14H11N 87.01 5.74 7.25
Example 2
Preparation of 4'-bromomethyl-2-cyanobiphenyl (III)
2-cyano-4'-methylbiphenyl (II) (0.97 g, 0.005 mol), 48% aqueous hydrobromic acid (0.004 g), and cyclohexane (8 ml) was refluxed till a clear solution was obtained. To this solution was added 2, 2'-azobisisobutyronitrile (0.17 g, 0.001 mol). A small portion of suspension containing N-bromosuccinimide (1.1 g, 0.006 mol) in cyclohexane (8 ml) was then added. The reaction mixture turned orange. The remaining N-bromosuccinimide suspension in cyclohexane was now added in portions within 2 hours up to 70° C. The mixture was stirred for 1 hour and then cooled to 20 C. The mixture was filtered, and the residue was washed with cyclohexane, isopropanol, and warm water. Drying at 60° C afforded a colourless solid of 4'-bromomethyl-2-cyanobiphenyl (III). (1.18 gm, Yield = 87%). m.p. 115° C.
1H-NMR, (CDCI3), (300 MHz), δ (ppm): 4.499 (s, 2 H), 7.408-7.663 (m, 4H) 7.899-8.085 (m, 4H).
13C-NMR, (CDCI3), (75 MHz), δ (ppm): 33.074, 112.239, 119.980, 128.508, 128.619, 130.092, 134.063, 135.243, 135.480, 137.190, 137.321, 146.982.

MS (m/z): 272 (M+). Elemental analysis:
Elements %C %H % N
Found 61.62 3.61 5.05
Calculated for C14H10BrN 61.79 3.70 5.15
Example 3
Preparation of N-[(2'-cyanobiphenyl-4-yl)-methyl]-(s)-valine methyl ester (IV)
(s)-Valine methyl ester (0.524 g, 0.004 mol) was dissolved in acetonitrile (8 ml) in a 25 ml round bottom flask. To this mixture, potassium carbonate (2.21 g, 0.016 mol, 4 equivalents) and 4'-bromomethyl-2-cyanobipheny] (III) (1.1 g, 0.004 mol) were added. Reaction mixture was then refluxed for 2 hours at 60° C. After this period, it was cooled to room temperature and filtered. Solvent was recovered by vacuum distillation. This gave oil which was purified by column chromatography using silica gel (100 g) adsorbent. Elution with pet. ether : chloroform (70:30) in column chromatography followed by recovery of solvent afforded oil of of N-[(2'-cyanobiphenyl-4-yl)-methyl]-(s)-valine methyl ester (IV). (1.1 g m, Yield = 85%).
1H-NMR, (CDCI3), (300 MHz), δ(ppm): 0.991 (d, 6 H), 1.972 (m, 1 H), 3.085 (d, 1 H), 3.764 (s, 3 H), 3.921 (d, 2 H), 7.450-7.551 (m, 4H), 7.652-7.734 (m, 4 H).
13C-NMR, (CDCI3), (75 MHz), δ (ppm): 18.112,19.226, 32.131, 51.325, 52.326, 66.416, 111.242,118.432, 127.359, 128.524, 130.254, 133.364,134.412, 137.141, 138.761,141.301, 145.312, 175.115.
MS (m/z): 322 (M+).
Elemental Analysis:
Elements %C %H %N
Found 74.25 6.67 8.49
Calculated for C20H22N2O2 74.51 6.88 8.69
Example 4
Preparation of N-pentanoyl-N-[(2'-cyanobiphenyl-4-yl)-methyl]-(s)-valine methyl ester (V)
In a 100 ml round bottom flask pentanoic acid (0.37 g, 0.0033 mol), CoCI2.6H2O (5 mol%) and acetone (25ml) were taken. Into this mixture N-[(2'-cyanobiphenyl-4-yl)-methyl]-(s)-valine methyl ester (IV) (1.063 g, 0.0033 mol) was added. The reaction mixture was then refluxed for 12 hours. Acetone was recovered by distillation. The residue obtained was extracted with dichloromethane. The organic layer was washed with saturated aqueous NaHCO3, water and

dried over anhydrous sodium sulphate. This was followed by distillation under vacuum to afford yellow oil of N-pentanoyl-N-[(2'-cyanobiphenyl-4-yl)-methyl]-(s)-valine methyl ester (V) (1.286 g, Yield= 96%).
1H-NMR, (CDCI3), (300 MHz), δ (ppm): 0.901 (d, 6H), 0.943-0.976 (t, 3H), 1.252-1.2947 (m, 2H), 1.525-1.536 (m, 2H), 2.359-2.371 (t, 2H), 2.651-2.661 (m, 1H), 4.629 (d, 1H), 4.912 (s, 3H), 5.023- 5.221 (d, 2H), 7.368-7.498 (m, 4H), 7.634- 7.743 (m, 4H).
13C-NMR, (CDCI3),(75 MHz), δ (ppm): 14.145, 19.151,20.601,22.201,27.561,27.841, 33.325,45.512,52.251,61.345,111.124,118.114,128.371,129.231,130.145,133151,134.461, 137.631, 138.641, 139.338,145.465, 171.268, 175.467.
MS (m/z): 406 (M+).
Elemental Analysis:
Elements %C %H %U
Found 73.64 7.23 6.65
Calculated for C25H30N2O3 73.86 7.44 6.89
Example 5
Preparation of N-pentanoyl-N-[(2'-(lH-tertazol-5-yl)-biphenyl-4-yI)methyI]-(s)-vaIine methyl ester (VI)
N-pentanoyl-N-[(2-cyanobiphenyI-4-yl)methyl]-(s)-valine methyl ester (V) (1.26 g, 0.0031 mol), sodium azide (0.54 g, 0.0039 mol) and triethyl amine hydrochloride (0.2 lg, 0.0039 mol) were added to dry toluene (10 ml) in a 25 ml round bottom flask. Reaction mixture was refluxed for 24 hours with stirring. Then it was poured into cold water. The separated aqueous layer was acidified with 36% hydrochloric acid to give a solid. It was filtered and purified by crystallisation from alcohols (saturated aliphatic/ branched aliphatic), preferably ethanol to give colourless crystals of N-pentanoyl-N-[(2'-( 1 H-tertazol-5-yl)-biphenyl-4-yl)methyl]-(s)-vaIine methyl ester (VII). (l.lg, Yield=79%), m.p. 71 °C.
1H-NMR, (CDCI3), (300 MHz), δ (ppm): 0.842-0.873 (d, 6H), 0.952-1.015 (t, 3H), 1.234-1.299 (m, 2H), 1.391-1.434 (m, 2H), 2.211-2.262 (t, 2H), 2.330-2.421 (ra, 1H), 3.402 (s, 3H), 4.412 (d, 1H), 4.712 (d, 2H), 7.356-7.497 (m, 4H), 7.512-7.716 (m, 4H).
13C-NMR, (CDCI3), (75 MHz),δ (ppm): 14.102, 19.184, 20.341, 22.525, 27.175, 27.617, 33.524,46.251,52.371,62.432, 123.643, 128.431, 129.132, 130.715, 131.342, 137.246, 138.143, 138.651, 141.224, 141.941, 155.261, 171.472, 175.276.
MS (m/z): 449 (M+).

Elemental Analysis:
Elements %C %H %N
Found 66.55 6.70 15.35
Calculated for C25H31N5O3 66.79 6.95 15.58
Example 6
Preparation of N-pentanoyl-N-[(2 -(1 H-tertazol-5-yl)-biphenyl-4-yl)methyl]-(s)-valine (I)
N-pentanoyl-N-[(2'-(lH-tertazol-5-yl)-biphenyl-4-yl)methyl]-(s)-valine methyl ester (VI) (1.08 g, 0.0024 mol) was added to a solution of potassium hydroxide (85%) (0.16 g, 0.0029 mol), methanol (10 ml) and water (1 ml) in a 25 ml round bottom flask. The reaction mixture was refluxed for 2 hours. Methanol was recovered by vacuum distillation, water (5 ml) was added to the residue and extracted with dichloromethane (20 ml x 3). Separated organic layer was dried over sodium sulphate and filtered. Recovery of solvent by distillation afforded white solid. It was purified by crystallisation from alcohols (saturated aliphatic/ branched aliphatic), preferably isopropanoi to give colourless crystals of N-pentanoyl-N-[(2 -(lH-tertazol-5-yl)-biphenyl-4-vl)methyl]-(s)-valine (I). (1.002 g, Yield= 96 %), m.p. 116 °C, [a]D= (-) 66.8° (1% MeOH, 20 °C).
'H-NMR, (CD3OD), (300 MHz), δ (ppm): 0.855 (d, 6H), 1.013 (t, 3H), 1.257 (m, 2H), 1.531 (m, 2H), 2.365 (t, 2H), 2.658 (m, 1H), 4.637 (d, 1H), 4.735 (d, 2H), 5.144 (broad singlet, NH), 7.027-7.281 (m, 4H), 7.527-7.716 (m, 4H), 12.310 (broad singlet of-OH of-COOH).
13C-NMR, (CD3OD), (75 MHz),δ (ppm): 12.865,18.095, 19.273, 22.074, 27.223, 27.877, 33.051,53.611,66.567, 122.951, 127.518, 128.996,130.278, 131.171,137.394,138.131, 138.308, 141.729, 141.858, 155.357, 171.588, 175.611.
MS (m/z): 435 (M+).
Elemental Analysis:
Elements %C %H %N
Found 66.05 6.60 15.85
Calculated for C24H29N5O3 66.19 6.71 16.08

We Claim:
1. A process of preparing Valsartan (I) and its intermediates comprising the following steps,
(a) Synthesis of 2-cyano-4'-methylbiphenyl (II) from 2-aminobenzonitrile, t-butyl nitrite and toluene as illustrated in example 1.
(b) Synthesis of 4'-bromomethyl-2-cyanobiphenyl (III) by brominating 2-cyano-4'-methylbiphenyl (II) with N-bromosuccinimide, as illustrated in example 2.
(c) Synthesis of N-[(2'-cyanobiphenyl-4-yl)-methyl]-(s)-valine methyl ester (IV) by reaction of 4'-bromomethyl-2-cyanobiphenyl (III) with (s)-valine methyl ester, as illustrated in example 3.
(d) Synthesis of N-pentanoyl-N-[(2'-cyanobiphenyl-4-yl)-methyl]-(s)-valine methyl ester (V) from N-[(2'-cyanobiphenyl-4-yl)-methyl]-(s)-valine methyl ester (IV) and pentanoic acid in presence of CoCI2.6H2O catalyst, as illustrated in example 4.
.(e) Synthesis of N-pentanoyl-N-[(2'-(lH-tertazol-5-yl)-biphenyl-4-yl)methyl]-(s)-valine methyl ester (VI) from N-pentanoyl-N-[(2'-cyanobiphenyl-4-yl)-methyl]-(s)-valine methyl ester (V), NaN3, and Et3N.HCI, as illustrated in example 5.
(f) Synthesis of N-pentanoyl-N-[(2 -(lH-tertazol-5-yl)-biphenyl-4-yl)methyl]-(s)-valine (I) by alkaline hydrolysis N-pentanoyl-N-[(2'-(lH-tertazol-5-yl)-biphenyl-4-yl)methyl]-(s)-valine methyl ester (VI), as illustrated in example 6.
2. A process of preparing Valsartan (I) and its intermediates such as herein described.