HCID 68512093, compound → 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

HRID 2241271Notes

Reaction equation

HRID 2241271 reaction equation
[CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][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](I)=[N:9]2)=[CH:5][CH:4]=1.[CH3:44][N:45]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[O:53][CH:54]=[C:55]([Sn](CCCC)(CCCC)CCCC)[CH:56]=2)[CH2:47][CH2:46]1.BrC1C=C(CN2CCN(C)CC2)OC=1[Sn](CCCC)(CCCC)CCCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][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:55]3[CH:56]=[C:52]([CH2:51][N:48]4[CH2:47][CH2:46][N:45]([CH3:44])[CH2:50][CH2:49]4)[O:53][CH:54]=3)=[N:9]2)=[CH:5][CH:4]=1

Participants

6

Reactant 3

HCID 68512093HCID 68512093, compoundHCID 685121811-((4-Bromo-5-(tributylstannyl)furan-2-yl)methyl)-4-methylpiperazineHCID 685132471-Methyl-4-((4-(tributylstannyl)furan-2-yl)methyl)piperazine

Product 1

HCID 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-dicarboxamide

Reagents, catalysts & solvents 2

HCID 178418476HCID 178418476, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

A stirred mixture of N-(4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (35 mg, 0.0503 mmol) and a 14:86 mixture of 1-methyl-4-((4-(tributylstannyl)furan-2-yl)methyl)piperazine and 1-((4-bromo-5-(tributylstannyl)furan-2-yl)methyl)-4-methylpiperazine (26.0 mg, 0.0554 mmol, prepared in Example 66, Step B) in dioxane (0.5 mL) was sparged with N2 for 2 minutes. PdCl2(PPh3)2 (2 mg, 0.003 mmol) was added, and the reaction was heated to 90° C. for 18 hours in a sealed vessel. After cooling to ambient temperature, the crude reaction mixture was loaded directly on to a preparative TLC plate (0.5 mm thickness, Rf=0.60) eluting with 90:10 CHCl3/MeOH (containing 7N NH3). Isolated product as an off-white solid (27 mg, 83:17 mixture of 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 and 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 by 1H-NMR). The mixture of products were carried forward without further purification.

Workup

  1. customwas sparged with N2 for 2 minutes
  2. temperatureAfter cooling to ambient temperature
  3. customthe crude reaction mixture
  4. washeluting with 90:10 CHCl3/MeOH (containing 7N NH3)
  5. additionThe mixture of products
  6. customwere carried forward without further purification

Sources & evidence

ORD record
ord-4744a2733cee43a9860355f5079c96c4
Source dataset
uspto-grants-2010_05
Patent number
US07723330B2

Reaction notes

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