p-Tolunitrile → Letrozole

Participants

Reaction Conditions

Reaction Steps

A glass reactor was charged with 24.3 grams of 1,2,4-triazolylsodium and 500 grams of dimethylformamide. At a temperature between −10° C. and 0° C., 50 grams of 4-(bromomethyl)benzonitrile (53.2 grams with a purity of about 94 percent by weight, containing about 6 percent by weight of 4-tolunitrile) were added in portions. After stirring at 0° C. for 1 hour, 30.9 grams of 4-fluorobenzonitrile were added, and, while maintaining a temperature of −5° C. to −10° C., 245 grams of a 40 percent solution of sodium bis(trimethylsilyl)amide in THF were added dropwise. After the addition was completed, the reaction was quenched by the addition of 200 grams of 50 percent acetic acid, followed by precipitation of the product by the addition of 1500 grams of water. The resulting suspension was stirred and cooled to about 15° C., and the precipitate was collected and rinsed with water. The wet precipitate was dissolved in 350 grams of dichloromethane, and the solution washed with 250 grams of water. The organic phase was separated, concentrated to a volume of about 200 ml, diluted with 250 grams of toluene, and concentrated to a volume of about 300 ml. The resulting suspension was stirred at ambient temperature for 1 hour, and the precipitate was collected, rinsed with toluene, and dried, yielding 52 grams of crude letrozole product.

Provenance & Evidence