Patent ID: 8198460

Claim:
A process for preparation of Letrozole of formula (I), having a purity of ≧99%, comprising the steps of: i) addition of 1H-1,2,4-triazole of formula (III), over a period of 1 to 4 hours to a mixture of 4-bromomethyl benzonitrile of formula (II), an alkali metal carbonate, and an organic solvent, at a temperature between 20° to 50° C.; ii) heating the mixture of step i) at a temperature of between 50° to 110° C., for a period of 2 to 4 hours, till completion of reaction; iii) cooling of the mixture of step ii) to ambient temperature and removal of the alkali metal carbonate by filtration; iv) evaporation of the solvent from the filtrate of step iii) and dissolving the residue in ethyl acetate or diluting the filtrate of step iii) with ethyl acetate; v) washing of the ethyl acetate solution of step iv), containing 4-[1-(1,2,4-triazolyl) methyl]-benzonitrile of formula (IV), two to three times with water and separation of the ethyl acetate layer; vi) cooling the ethyl acetate solution of step v) to a temperature of between 0° to 10° C.; vii) addition of a solution of isopropanol-hydrochloride to the solution of step vi) at a temperature of between 0° to 5° C. over a period of between 45 to 90 minutes to adjust the pH in the range of 0 to 2; viii) agitation of the mixture of step vii) at a temperature of between 0° to 5° C. for period of between 1 to 2 hours; ix) isolation of 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile hydrochloride of formula (VII) by filtration; x) optionally dissolving the solid of step ix) in ethyl acetate and treating the solution with a base to obtain 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile of formula (IV), and further treating the solution with isopropanol-hydrochloride, followed by isolation of the precipitated 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile hydrochloride of formula (VII) by filtration; xi) drying the solid of step ix) or step x) to obtain 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile hydrochloride of formula (VII), having a purity of ≧99%; xii) addition of a solution of 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile hydrochloride of formula (VII), as obtained in step xi) in a dipolar aprotic solvent to a solution of potassium tertiarybutoxide in the same dipolar aprotic solvent, over a period of 30 to 60 minutes, at a temperature between −25° to 5° C.; xiii) agitation of the mixture of step xii) at a temperature between −25° C. to 5° C. for a period of between 1 to 2 hours; xiv) addition of a solution of 4-fluorobenzonitrile of formula (VI), in a dipolar aprotic solvent to the mixture of step xiii) over a period of 1 to 2 hours at a temperature of between −25° C. to 5° C.; xv) agitation of the mixture of step xiv) at a temperature of between −25° to 5° C. for a period of between 1 to 2 hours; xvi) isolation of Letrozole of formula (I) from the mixture of step xv); and xvii) drying the solid obtained from step xvi) to give Letrozole of formula (I), having a purity of ≧99%.