FIELD OF INVENTION

The invention relates to an improved process for the preparation of 2-Cyano-4'-formyl biphenyl of
Formula I

which is useful as an Intermediate in the preparation of Valsartan.

BACKGROUND OF INVENTION

Valsartan, also known as (S)--N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl- )bi phenyl-4-ylmethyl]-amine and is marketed as the free acid under the name DIOVAN. Valsartan and/or its intermediates are disclosed 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), Valsartan is an orally active specific angiotensin II antagonist acting on the ATI receptor subtype. Valsartan is prescribed for the treatment of hypertension.
In US patent 5,399,578, 2'-Cyano-4-formyl-biphenyl is produced by oxidation of 2'-Cyano-4-hydroxymethyl-biphenyl with Oxalyl chloride, dimethyl sulfoxide, and Triethyl amine in dichloromethane solution . This procedure is the well known Swern oxidation, which produces extremely malodorous dimethyl sulfide as a by product, use of this procedure on a commercial scale requires costly and inefficient measures to prevent release of objectionable quantities of dimethyl sulfide. In addition, the oxalyl chloride used in the Swern oxidation is moisture sensitive, irritation and toxic. The major problem associated with these reaction conditions from an industrial view point is use of cryogenic temperatures (-60°C). The scheme is shown below.


These are major disadvantages associated with the procedure described in the above mentioned patent.
OBJECTIVE OF THE INVENTION
An object of the present invention is to provide a process for the preparation of2-Cyano-4'-formyl biphenyl of Formula I.
SUMMARY OF THE INVENTION
The instant invention discloses an improved and efficient method for the preparation of 2-Cyano-4'-formyl biphenyl compound of the formula I
which comprises,
(i) By the Oxidation of 4'-(Hydroxy mefhyl)biphenyl-2-carbonitrile compound of formula II

with sodium hypo chlorite using TEMPO (2,2,6,6-tetramethyl-l-piperidinyloxy free
radical).

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates, to an improved process for preparation of 2'--Cyano-4-
formyl-biphenyl, which is a key intermediate for the synthesis of Valsartan.
The process of invention includes oxidation of 2'-Cyano-4-hydroxymethyl-biphenyl with
an oxidizing agent like sodium hypochlorite using a nitroxil compound 2,2,6,6-
tetramethyl-1-piperidinyloxy free radical (TEMPO) as catalyst at -10°C to -15°C
temperatures.
EXAMPLE
To a solution of 0.2g of 2,2,6,6-tetramethyl-l-piperidinyloxy free radical(TEMPO) and 4g of potassium bromide in 250 mL methylene chloride was added 50g (0.238 mol) of 2'-Cyano-4-hydroxymethyl-biphenyl, in 1000 ml methylene chloride at -10 to -15 °C. Stirr for 5 minutes add 240mL (pH=T0) of sodium hypochlorite solution over 90minutes at -10 to -15 °C with stirring. After 3 hours of additional stirring, check TLC, quench the reaction mass in to solution of 1.5% hydrose solution (1000 mL) and the organic layer was separated. The aqueous layer was extracted twice with 1 OOmL of methylene chloride, and the collected organic layer washed thrice with 600mL DM water and sodium chloride washing , dried the organic layer and evaporated to give crude compound which on recrystallization with hexanes (200mL) to yield 45g of colorless solid compound 2'-. Cyano-4-formyl-biphenyl.
Yield: 88%; purity (determined by HPLC):99%.
1H NMR data (300MHz, CDC13, ppm): 7.50-8.33 (m, 8H), 10.14(1H, s)
MS (ES~): 206.3(M-1)

CLAIMS:
1. An improved process for the preparation of 2-Cyano-4'-formyl biphenyl compound
of the formula I
which comprises ,
a. By the Oxidation of 4'-(Hydroxy methyl)biphenyl-2-carbonitrile compound of formula II

with sodium hypo chlorite using TEMPO (2,2,6,6-tetramethyl-l-piperidinyloxy free radical) as a catalyst.
2. The process according to claim 1, where the reaction is carried out in the presence of an organic solvent.
3. The process according to claim 2, where an organic solvent is halogenated hydrocarbon like methylene dichloride, chloroform, etc. More preferably Methylene dichloride is used.