Irbesartan is a non-peptide angiotensin-K antagonist, which inhibits the action of angiotensin-II on its receptor and thus prevents the increase in blood pressure produced by the hormone-receptor interaction. Irbesartan is, therefore, employed in the treatment of cardiovascular complaints, such as hypertension, diabetic neurotherapy and heart failure. The current pharmaceutical product containing this drug is being sold by Sanofi Synthelabo using the tradename AVAPRO, in the form of tablets.
Irbesartan is known by the following chemical names:    a) 2-Butyl-3-[[2′-(1H-tetrazol-5-yl) [1,1′-biphenyl]-4-yl]methyl]-1,3-diazaspiro[4,4]non-1-en-4-one    (b) 2-Butyl-3-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]-1,3-diazaspiro[4,4]non-1-en-4-one    (c) 2-n-butyl-4-spirocyclopentane-1-[(2′-(tetrazol-5-yl) biphenyl-4-yl) methyl]-2-imidazolin-5-one
The synthesis of irbesartan is first disclosed in U.S. Pat. No. 5,270,317 (equivalent EPO454511) and subsequently, several other patents disclose the synthesis of irbesartan by different methods. Basically the synthesis of this molecule involves two common intermediates namely spiroimidazole of formula III and substituted halomethyl-biphenyl compound of formula IV.

U.S. Pat. No. 5,270,317 (hereinafter referred to as '317 patent) describes a process for preparation of irbesartan which involves condensation of the Spiro compound of Formula III with halomethyl-cyanobiphenyl compound of Formula IV in presence of an inert solvent such as N,N-dimethylformamide, Dimethylsulfoxide or tetrahydrofuran with a basic reagent for example sodium hydride, or triethyl amine to produce formula II i.e. cyano derivative which is further reacted with tributyltin azide and trityl chloride followed by deprotection with HCl to produce Irbesartan. The yield of Irbesartan obtained is very poor and the process involves column chromatographic purifications. Methods involving column chromatographic purifications are generally undesirable for large-scale operations, thereby making the process commercially unfeasible. The process used in '317 patent also suffers from disadvantages such as high cost of reagents, the use of additional reagents such as tributyltin azide and trityl chloride, low yields of the product, extra purification steps to obtain the final product and health hazards. The use of tributyltin azide is not advisable for scale up operations.
U.S. Pat. Nos. 5,352,788 and 5,559,233 also describe identical alkylation of Formula III with the halo-biphenyl compound using the same inert solvent and the same basic reagents.
U.S. Pat. No. 6,162,922 describes a process for preparation of irbesartan which involves treating the spiro intermediate of Formula III with halomethyl-cyanobiphenyl intermediate of Formula IV in presence of a water immiscible organic solvent, a base and a phase transfer catalyst.
WO2007/013101 describes a process for preparation of irbesartan which involves condensation of the Spiro compound of Formula III with halomethyl-biphenyl compound of Formula IV in presence of base and a mixture of polar aprotic and non polar solvents to get the intermediate of Formula IV. The '922 patent uses a mixture of organic solvents comprising of toluene, xylene, DMF or DMSO.
WO2006/046043 describes a one-pot process for preparation of irbesartan which comprises reacting Formula III optionally in salt form with a derivative of formula IV wherein instead of cyano group a trityl protected tetrazole group is present. The reaction is carried out in the presence of a base and a phase transfer catalyst in a hydrocarbon solvent, preferably toluene and optionally in presence of water as a second phase of the one-pot reaction system.
All of the above identified patents describe alkylation in polar aprotic solvents, non-polar solvents or a mixture thereof in the presence of a basic reagent etc. Further the processes known in the prior art for preparing Irbesartan involves tedious workup procedures, e.g. a large number of steps, which includes the protection and subsequent deprotection, and isolation of intermediates, as well as separation by column chromatography and this results in excessive production time, which in turn renders the process more costly and less eco-friendly; thus the processes are not suitable for commercial scale up. The prior art processes further involves use of high boiling solvents in which the recovery of solvent is also difficult that leads to special increase the high effluent treatment load, feasibility and high recovery cost.
In light of above disadvantages there remains a need for a simple, commercially advantageous and industrially viable process for the preparation of Irbesartan intermediates.
The present inventors have surprisingly developed an improved process for the synthesis of one of the key intermediates leading to irbesartan and subsequently a one pot process via the said intermediate which ameliorates the drawbacks of the prior art. The present inventors have surprisingly found that conducting the alkylation reaction in a single phase system with the optional use of phase transfer catalysts yields a product of formula II which can be extracted in a water immiscible solvent and directly used for further steps to provide Irbesartan in high purity and good yield. The present inventors have also found that generation of solid waste is minimized by the presence of aqueous phase in the reaction medium The present inventors have further surprisingly found that the one pot process employed in the present invention helps in the reduction of time and provides Irbesartan with high yield and purity.