Diisopropylethylamine → N-(4-(2-(4-methoxybenzylamino)pyridin-4-yloxy)-2-fluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

HRID 476374Notes

Reaction equation

HRID 476374 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:41]=[CH:40][C:22]([CH2:23][NH:24][C:25]2[CH:30]=[C:29]([O:31][C:32]3[CH:37]=[CH:36][C:35]([NH2:38])=[C:34]([F:39])[CH:33]=3)[CH:28]=[CH:27][N:26]=2)=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][NH:24][C:25]2[CH:30]=[C:29]([O:31][C:32]3[CH:37]=[CH:36][C:35]([NH:38][C:14]([C:11]4([C:9]([NH:8][C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)=[O:10])[CH2:12][CH2:13]4)=[O:16])=[C:34]([F:39])[CH:33]=3)[CH:28]=[CH:27][N:26]=2)=[CH:40][CH:41]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 210815301-[(4-Fluorophenyl)carbamoyl]cyclopropanecarboxylic AcidHCID 66605351N-(4-methoxybenzyl)-4-(4-amino-3-fluorophenoxy)pyridin-2-amine

Product 1

HCID 66604557N-(4-(2-(4-methoxybenzylamino)pyridin-4-yloxy)-2-fluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideYield 57%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

1-((4-Fluorophenyl)carbamoyl)cyclopropanecarboxylic acid (see Example B1, 171 mg, 0.77 mmol), N-(4-methoxybenzyl)-4-(4-amino-3-fluorophenoxy)pyridin-2-amine (see PCT Publication No. WO 2008/046003, 200 mg, 0.59 mmol), TBTU (284 mg, 0.88 mol) and DIEA (0.12 ml, 0.73 mmol) were combined in DMF (1.5 mL) and the resultant mixture was stirred overnight. The reaction mixture was partitioned between saturated aqueous NaHCO3 (20 mL) and EtOAc (20 mL). The organic was washed with water (10 mL), brine (10 mL), and 5% aqueous lithium chloride solution (10 mL), and was then dried over MgSO4 and concentrated in vacuo. Dichloromethane was added to the residue and the resultant slurry was filtered. The collected precipitate was washed with CH2Cl2 and dried in vacuo to provide N-(4-(2-(4-methoxybenzylamino)pyridin-4-yloxy)-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (137 mg) as a white solid. The filtrate was concentrated and a second crop (46 mg, total yield 57%) was collected. MS (ESI) m/z: 545.1 (M+H+).

Workup

  1. customThe reaction mixture was partitioned between saturated aqueous NaHCO3 (20 mL) and EtOAc (20 mL)
  2. washThe organic was washed with water (10 mL), brine (10 mL), and 5% aqueous lithium chloride solution (10 mL)
  3. dry with materialwas then dried over MgSO4
  4. concentrationconcentrated in vacuo
  5. additionDichloromethane was added to the residue
  6. filtrationthe resultant slurry was filtered
  7. washThe collected precipitate was washed with CH2Cl2
  8. customdried in vacuo

Sources & evidence

ORD record
ord-0ba6a75f417f47d8bcf7da4e51d0c68e
Source dataset
uspto-grants-2014_01
Patent number
US08637672B2

Reaction notes

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