Hydrochloric Acid → Anastrozole

Participants

Reaction Conditions

Reaction Steps

4-Amino-1-[3,5-bis-(1-cyano-1-methylethyl)benzyl]-1H-[1,2,4]triazolium bromide (5) (70 g) was dissolved in cone. HCl (280 mL) in a 5 L R.B. flask and cooled to −5° C. A solution of sodium nitrite (15 g) in water (70 mL) was slowly added to the reaction mixture at 0-5° C. in 4 hrs and the reaction mixture was stirred for one hour at 0-5° C. and further at 10-20° C. for next 3 hours. The reaction mixture was quenched by the addition of a solution of urea (4.5 g) in water (15 mL). Toluene (700 mL) was added to the reaction mixture and the heterogeneous solution was further cooled down to 0-5° C. The solution was basified by the addition of liquor ammonia (365 mL) slowly in 4 hours at 5-25° C. Organic layer was separated and further washed with water (200 mL). Aqueous layer was removed and a solution of cone. HCl (140 mL) in water (140 mL) was added to the organic layer slowly in 30 minutes at 25-30° C. and reaction mass was heated at 60-65° C. for 30 minutes. The lower aqueous layer (280-300 mL), containing product was collected in a conical flask maintaining at 50° C. The aqueous part was again washed with toluene (700 mL) at 60-65° C. for 30 minutes. The lower aqueous layer, containing product was charged in a separating funnel and again washed with fresh toluene (700 mL). The aqueous layer, containing product was transferred in a R.B. flask and ethyl acetate (350 mL) was added to it. The heterogeneous solution was cooled to 0-5° C. basified by the slow addition of liquor ammonia (280 mL) in 2-3 hours at 5-25° C. The solution was stirred for one hour at 25-35° C., and the upper organic layer (360-375 mL), containing product was separated and filtered through hyflow super cell bed. Solvent was distilled out below 50° C. under vacuum leaving approximately 100 mL ethyl acetate in the flask. The content of the flask was cooled down to 25-35° C. and cyclohexane (500 mL) was added to the solution slowly in 30 minutes. The precipitated solid product was filtered and washed with fresh cyclohexane (20 mL×2). The product was dried at 45-50° C. to get crude Anastrozole (44 g) with more than 98% HPLC purity contaminated with related substance (6) as 0.36% and with related substance (7) as 0.05%.

Provenance & Evidence