Trifluoroacetic acid → 5,6-difluoro-N-(4-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine

HRID 252651Notes

Reaction equation

HRID 252651 reaction equation
[F:1][C:2]1[C:34]([F:35])=[CH:33][C:5]2[NH:6][C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]4[C:22]([C:23]5[CH:28]=[CH:27][N:26]=[C:25](S(C)(=O)=O)[N:24]=5)=[CH:21][CH:20]=[CH:19][N:18]=4)=[CH:12][CH:11]=3)=[N:8][C:4]=2[CH:3]=1.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:43]2[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=2)[CH2:39][CH2:38]1.C(O)(C(F)(F)F)=O>CC(O)C>[F:1][C:2]1[C:34]([F:35])=[CH:33][C:5]2[NH:6][C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]4[C:22]([C:23]5[CH:28]=[CH:27][N:26]=[C:25]([NH:49][C:46]6[CH:45]=[CH:44][C:43]([N:40]7[CH2:39][CH2:38][N:37]([CH3:36])[CH2:42][CH2:41]7)=[CH:48][CH:47]=6)[N:24]=5)=[CH:21][CH:20]=[CH:19][N:18]=4)=[CH:12][CH:11]=3)=[N:8][C:4]=2[CH:3]=1

Participants

5

Reactant 3

HCID 6422Trifluoroacetic acidHCID 7372534-(4-Methylpiperazin-1-yl)anilineHCID 668629535,6-difluoro-N-(4-(3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine

Product 1

HCID 589669685,6-difluoro-N-(4-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
90 °C

Procedure

A resealable pressure bottle, under nitrogen, was charged with 5,6-difluoro-N-(4-(3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine (0.13 g, 0.26 mmol), 4-(4-methylpiperazin-1-yl)benzenamine (0.25 g, 1.31 mmol), TFA (0.12 ml, 1.58 mmol), and 2-propanol (10.00 ml, 0.03 M). The reaction vessel was sealed and the mixture stirred at 90° C. for 4 days. The reaction mixture was cooled to RT and concentrated to brown residue. The residue was purified by Biotage silica gel chromatography (2%-8% MeOH/Dichloromethane) followed by Gilson reverse phase chromatography (10% to 90% CH3CN/H2O/0.1% TFA). The product-containing fractions were combined, basified by addition of aq. NaHCO3 and extracted with ethyl acetate. The organic portion was dried with Na2SO4, filtered, and concentrated to afford 5,6-difluoro-N-(4-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine as a yellow solid. MS m/z=606.1 [M+H]+. Calc'd for C33H29F2N9O: 605.64.

Workup

  1. customThe reaction vessel was sealed
  2. temperatureThe reaction mixture was cooled to RT
  3. concentrationconcentrated to brown residue
  4. customThe residue was purified by Biotage silica gel chromatography (2%-8% MeOH/Dichloromethane)
  5. additionbasified by addition of aq. NaHCO3
  6. extractionextracted with ethyl acetate
  7. dry with materialThe organic portion was dried with Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated

Sources & evidence

ORD record
ord-135dc7b8cab2487b8a8fc0e6e46d2af6
Source dataset
uspto-grants-2011_01
Patent number
US07868177B2

Reaction notes

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