Trifluoroacetic acid → HCID 178480815, compound

HRID 2241272Notes

Reaction equation

HRID 2241272 reaction equation
COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]([C:33]5[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=5)[C:25]([C:27]5([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]5)=[O:26])=[CH:20][C:19]=4[F:40])=[C:11]3[C:10]([C:41]3[CH:45]=[C:44]([CH2:46][N:47]4[CH2:52][CH2:51][N:50]([CH3:53])[CH2:49][CH2:48]4)[O:43][CH:42]=3)=[N:9]2)=CC=1.COC1C=CC(CN2C3=NC=CC(OC4C=CC(N(C5C=CC(F)=CC=5)C(C5(C(N)=O)CC5)=O)=CC=4F)=C3C(C3OC(CN4CCN(C)CC4)=CC=3Br)=N2)=CC=1.C(O)(C(F)(F)F)=O>>[F:40][C:19]1[CH:20]=[C:21]([N:24]([C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)[C:25]([C:27]2([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[C:10]([C:41]3[CH:45]=[C:44]([CH2:46][N:47]4[CH2:52][CH2:51][N:50]([CH3:53])[CH2:49][CH2:48]4)[O:43][CH:42]=3)[C:11]=12

Participants

4

Reactant 3

HCID 6422Trifluoroacetic acidHCID 68512150N-(4-(1-(4-methoxybenzyl)-3-(5-((4-methylpiperazin-1-yl)methyl)furan-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideHCID 68516486N-(4-(1-(4-methoxybenzyl)-3-(3-bromo-5-((4-methylpiperazin-1-yl)methyl)furan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

Product 1

HCID 178480815HCID 178480815, compound

Procedure

A 17:83 mixture of N-(4-(1-(4-methoxybenzyl)-3-(5-((4-methylpiperazin-1-yl)methyl)furan-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and N-(4-(1-(4-methoxybenzyl)-3-(3-bromo-5-((4-methylpiperazin-1-yl)methyl)furan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)-cyclopropane-1,1-dicarboxamide (26 mg, 0.035 mmol) were heated with TFA (0.5 mL) at 80° C. for 2 hours in a sealed vessel. After cooling to ambient temperature, the mixture was concentrated in vacuo, using toluene to azeotrope. The resulting solid was portioned between EtOAc (5 mL) and 1:1 saturated aqueous NaHCO3/water (5 mL). The phases were separated, and the aqueous phase was re-extracted with EtOAc. The combined organic phases were washed with brine (5 mL), dried (Na2SO4), filtered, and concentrated. The crude products were separated by preparative TLC (0.5 mm thickness; N-(4-(3-(3-bromo-5-((4-methylpiperazin-1-yl)methyl)furan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide: Rf=0.33; N-(3-fluoro-4-(3-(5-((4-methylpiperazin-1-yl)methyl)furan-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide: Rf=0.25), eluting with 10% MeOH (containing 7N NH3) in CHCl3. The product, N-(3-fluoro-4-(3-(5-((4-methylpiperazin-1-yl)methyl)furan-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, was obtained as a white powder (1 mg, 5%). HPLC: 98% purity (254 nm); LRMS (ESI+): 100% purity, 220 nm, 628 m/z (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 8.32 (d, J=5 Hz, 1H), 8.18 (m, 2H), 7.77 (m, 1H), 7.45 (m, 2H), 7.24 (m, 1H), 7.07 (t, J=9 Hz, 2H), 6.92 (s, 1H), 6.32 (d, J=5 Hz, 1H), 3.62 (s, 2H), 2.64 (br s, 8H), 2.37 (s, 3H), 1.83 (m, 2H), 1.63 (m, 2H).

Workup

  1. concentrationthe mixture was concentrated in vacuo
  2. customThe phases were separated
  3. extractionthe aqueous phase was re-extracted with EtOAc
  4. washThe combined organic phases were washed with brine (5 mL)
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude products were separated by preparative TLC (0.5 mm thickness; N-(4-(3-(3-bromo-5-((4-methylpiperazin-1-yl)methyl)furan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide: Rf=0.33; N-(3-fluoro-4-(3-(5-((4-methylpiperazin-1-yl)methyl)furan-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide: Rf=0.25)
  9. washeluting with 10% MeOH (containing 7N NH3) in CHCl3

Sources & evidence

ORD record
ord-16ac8ff451804ce680a52540813162f7
Source dataset
uspto-grants-2010_05
Patent number
US07723330B2

Reaction notes

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