4-Fluoroaniline → N-(4-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

HRID 2241184Notes

Reaction equation

HRID 2241184 reaction equation
[CH3:1][O:2][C:3]1[CH:27]=[CH:26][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]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.FC1C=CC([NH:35][C:36]([C:38]2([C:41](O)=[O:42])[CH2:40][CH2:39]2)=[O:37])=CC=1.C1(C(O)=O)(C(O)=O)CC1.[F:53][C:54]1[CH:60]=[CH:59][C:57](N)=[CH:56][CH:55]=1.Cl.C(N=C=NCCCN(C)C)C>CC(N(C)C)=O.CCOC(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][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:57]5[CH:59]=[CH:60][C:54]([F:53])=[CH:55][CH:56]=5)[C:41]([C:38]5([C:36]([NH2:35])=[O:37])[CH2:39][CH2:40]5)=[O:42])=[CH:20][C:19]=4[F:25])=[C:11]3[CH:10]=[N:9]2)=[CH:26][CH:27]=1

Participants

9

Reactant 5

HCID 97314-FluoroanilineHCID 690171,1-Cyclopropanedicarboxylic acidHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 210815301-[(4-Fluorophenyl)carbamoyl]cyclopropanecarboxylic AcidHCID 685158574-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine

Product 1

HCID 68515238N-(4-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideYield 33%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 31374DimethylacetamideSolvent

Procedure

To a stirred mixture of 4-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (73 mg, 0.20 mmol; obtained from Example 1, Step D) and ((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic acid (49 mg, 0.220 mmol; prepared from cyclopropane-1,1-dicarboxylic acid and 4-fluoroaniline using the methods of WO 2005/030140 and by Shih and Rankin, Synth. Comm. 1996, 26(4), 833-836) in DMA (2 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (EDCI) (77 mg, 0.400 mmol). The reaction was stirred for 1 hour at room temperature. The reaction was diluted with EtOAc (10 mL) and water (10 mL). The phases were separated, and the organic phase washed with water (3×10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude was purified by preparative TLC eluting with 3% MeOH/DCM. The product was obtained as a waxy solid (42 mg, 33%). 1H NMR (400 MHz, CDCl3) δ 9.97 (s, 1H), 8.36 (d, J=5 Hz, 1H), 8.20 (s, 1H), 7.77 (m, 2H), 7.46 (m, 2H), 7.26 (m, 4H), 7.06 (m, 2H), 6.83 (d, J=9 Hz, 2H), 6.40 (d, J=5 Hz, 1H), 5.62 (s, 2H), 3.76 (s, 3H), 1.79 (m, 2H), 1.62 (m, 2H, overlaps with water).

Workup

  1. customThe phases were separated
  2. washthe organic phase washed with water (3×10 mL), brine (10 mL)
  3. dry with materialdried (Na2SO4)
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe crude was purified by preparative TLC
  7. washeluting with 3% MeOH/DCM

Sources & evidence

ORD record
ord-bac80c939f5c420d998efd8a61106991
Source dataset
uspto-grants-2010_05
Patent number
US07723330B2

Reaction notes

Loading…