4-Fluorobenzonitrile → Letrozole
Reaction equation
[N:1]1([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH:5]=[N:4][CH:3]=[N:2]1.F[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>>[C:11]([C:10]1[CH:13]=[CH:14][C:7]([CH:6]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:8][CH:9]=1)#[N:12]Participants
Procedure
U.S. Pat. No. 4,978,672 (referred to herein as '672, Indian Reference not available) provides 4-[alpha-(4-cyanophenyl)-1-(1,2,4-triazolyl)-methyl]benzonitrile and the process of its preparation. The patent discloses reacting 4-bromomethylbenzonitrile with 1,2,4-triazole to yield 4-[1-(1,2,4-triazol-1-yl)methyl]benzonitrile. 4-[1-(1,2,4-triazol-1-yl)methyl]benzonitrile is then reacted with 4-fluorobenzonitrile to give 4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile. This patent does not disclose the purity of 4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile, compound of formula 1. When we followed the patented process we also get the unwanted isomer 4-[1-(1,2,4-triazol-4-yl)methyl]benzonitrile, a compound of formula 4 (20 to 40%) in step 1. When the reaction mixture of step 1 is treated with 4-fluorobenzonitrile it yields 4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)-methyl]-benzonitrile, a compound of formula 1, and its isomer, a compound of formula 5. Thus the impurity of formula 4 has to be separated before treating it with 4-fluorobenzonitrile, which involves an additional step of column purification, which is reported in '672 and makes the process tedious and commercially unviable.
Sources & evidence
- ORD record
- ord-acaf3cf1e263474dbbeff6c5e497ea7b
- Source dataset
- uspto-grants-2008_12
- Patent number
- US07459565B2
Reaction notes
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