[NH:1]1[CH:5]=[N:4][C:3]([Na])=[N:2]1.Br[CH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.[C:17]1(C)[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=1.N1C=NC(CC2C=CC(C#N)=CC=2)=N1.FC1C=CC(C#N)=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.CC(N(C)C)=O>[CH:11]1[C:12]([C:13]#[N:14])=[CH:15][CH:16]=[C:9]([CH:8]([N:2]2[N:1]=[CH:5][N:4]=[CH:3]2)[C:17]2[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=2)[CH:10]=1A glass reactor was charged with 46 grams of 1,2,4-triazolylsodium and 1350 grams of dimethylacetamide. At a temperature between −15° C. and −10° C., 90 grams of 4-(bromomethyl)benzonitrile (95 grams of industrial grade having a purity of about 94 percent by weight, containing about 6 percent by weight of 4-tolunitrile) were added over a period of 30 minutes. After stirring at a temperature between −15° C. and −10° C. for 1 hour, and then at a temperature between −5° C. and 0° C. for 1 hour, an HPLC analysis indicated a ratio of intermediate III to isomer IV of 18:1. Then, 52.8 grams of 4-fluorobenzonitrile were added, and, while maintaining a temperature of −8° C. to 0° C., 480 grams of a 40 percent solution of sodium bis(trimethylsilyl)amide in THF were added dropwise. After the addition was completed, the reaction was stirred at a temperature between −2° C. and −2° C. for 1 hour, and then the reaction was quenched by the addition of a mixture of 180 grams of acetic acid and 540 grams of water, followed by precipitation of the product by the addition of 3510 grams of water. The resulting suspension was stirred overnight at ambient temperature, i.e., from 15° C. to 25° C., and then the precipitate was collected and rinsed with water. The wet precipitate was dissolved in 630 grams of dichloromethane and 63 grams of acetone, and the solution washed with 450 grams of water. The organic phase was separated at 30° C., diluted with 450 grams of toluene, concentrated at atmospheric pressure until all the dichloromethane was removed, and then further concentrated under vacuum to a weight of about 300 grams. The suspension was diluted with a further 450 grams of toluene and again concentrated under vacuum to a weight of 500 grams. The resulting suspension was stirred at a temperature between 10° C. and 15° C. for 1 hour, and the precipitate was collected, rinsed with toluene, and dried, yielding 99 grams of letrozole with a purity of 99.3 HPLC area percent. The only detectable impurity was 0.7 HPLC area percent of letrozole related compound A. The final purification of the letrozole product is described in Example 6.
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