反应详情

温度

-5 °C

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%.

1. customThe reaction mixture was quenched by the addition of a solution of urea (4.5 g) in water (15 mL)
2. additionToluene (700 mL) was added to the reaction mixture
3. temperaturethe heterogeneous solution was further cooled down to 0-5° C
4. additionThe solution was basified by the addition of liquor ammonia (365 mL) slowly in 4 hours at 5-25° C
5. customOrganic layer was separated
6. washfurther washed with water (200 mL)
7. customAqueous layer was removed
8. additionHCl (140 mL) in water (140 mL) was added to the organic layer slowly in 30 minutes at 25-30° C.
9. customreaction mass
10. temperaturewas heated at 60-65° C. for 30 minutes
11. customwas collected in a conical flask
12. temperaturemaintaining at 50° C
13. washThe aqueous part was again washed with toluene (700 mL) at 60-65° C. for 30 minutes
14. additionThe lower aqueous layer, containing product
15. additionwas charged in a separating funnel
16. washagain washed with fresh toluene (700 mL)
17. additionThe aqueous layer, containing product
18. additionflask and ethyl acetate (350 mL) was added to it
19. temperatureThe heterogeneous solution was cooled to 0-5° C.
20. additionbasified by the slow addition of liquor ammonia (280 mL) in 2-3 hours at 5-25° C
21. stirringThe solution was stirred for one hour at 25-35° C.
22. additionthe upper organic layer (360-375 mL), containing product
23. customwas separated
24. filtrationfiltered through hyflow super cell bed
25. distillationSolvent was distilled out below 50° C. under vacuum
26. customleaving approximately 100 mL ethyl acetate in the flask
27. temperatureThe content of the flask was cooled down to 25-35° C.
28. filtrationThe precipitated solid product was filtered
29. washwashed with fresh cyclohexane (20 mL×2)
30. customThe product was dried at 45-50° C.