Trifluoroacetic acid → HCID 178425785, compound
Reaction equation
[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:12][N:11]([C:13]([C:15]3[CH:16]=[CH:17][C:18]([CH3:40])=[C:19]([C:21]4[N:22]=[C:23]([CH:27]5[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]5)[NH:24][C:25]=4[CH3:26])[CH:20]=3)=[O:14])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:40][C:18]1[CH:17]=[CH:16][C:15]([C:13]([N:11]2[CH2:12][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[CH2:10]2)=[O:14])=[CH:20][C:19]=1[C:21]1[NH:22][C:23]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:24][C:25]=1[CH3:26]Participants
4
Procedure
To a solution of tert-butyl 4-(4-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-5-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate (compound 182.3, 475 mg, 0.88 mmol) in 20 mL CH2Cl2, was added trifluoroacetic acid (4 mL). The reaction stirred for 1.5 hours and concentrated under reduced pressure, neutralized with 10 mL Na2CO3 (1M) and lyophilized to afford 4-(1-(4-methyl-3-(4-methyl-2-(piperidin-4-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile. The mixture of 4-(1-(4-methyl-3-(4-methyl-2-(piperidin-4-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile (135 mg, 0.31 mmol), formic acid (300 μL, 6.76 mmol), formaldehyde (37% in water, 300 μL, 3.41 mmol) and water (1.5 mL) was heated to reflux for 10 hours. The reaction was diluted with saturated NaHCO3 until pH 9 and extracted with CH2Cl2 (3×20 mL). The residue was purified by preparative TLC with 10% methanol and 1% ammonium hydroxide in dichloromethane and lyophilized to give 43 mg (30% two steps) of the title compound as a white solid. m/z (ES+) 540 (M+H)+.