Diisopropylethylamine → N-(4-Fluorophenyl)-N'-[4-({2-[(pyrrolidin-1-ylcarbonyl)amino]pyridin-4-yl}oxy)phenyl]cyclopropane-1,1-dicarboxamide

HRID 2066298Notes

Reaction equation

HRID 2066298 reaction equation
[NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]2([C:36](O)=[O:37])[CH2:35][CH2:34]2)=[O:32])=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[F:23][C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:31]([C:33]2([C:36]([NH:1][C:2]3[CH:22]=[CH:21][C:5]([O:6][C:7]4[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]5[CH2:20][CH2:19][CH2:18][CH2:17]5)=[O:15])[CH:8]=4)=[CH:4][CH:3]=3)=[O:37])[CH2:35][CH2:34]2)=[O:32])=[CH:28][CH:29]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 210815301-[(4-Fluorophenyl)carbamoyl]cyclopropanecarboxylic AcidHCID 231532634-(4-Aminophenoxy)-2-[(pyrrolidin-1-yl)carbonylamino]pyridine

Product 1

HCID 59596956N-(4-Fluorophenyl)-N'-[4-({2-[(pyrrolidin-1-ylcarbonyl)amino]pyridin-4-yl}oxy)phenyl]cyclopropane-1,1-dicarboxamideYield 62%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

Pyrrolidine-1-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide (112 mg) and 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (87.4 mg) were dissolved in N,N-dimethylformamide (4 ml), and diisopropylethylamine (0.341 ml) and HBTU (203 mg) were added under a nitrogen atmosphere at room temperature, followed by stirring for 3 hr. The reaction mixture was partitioned after addition of ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml). The separated organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (30 ml) and brine (30 ml), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The resultant residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=1:7, then ethyl acetate). Fractions containing the target compound were concentrated under reduced pressure, and to the residue (133.0 mg) were added tert-butyl methyl ether (4 ml) and heptane (4 ml) to suspend a solid. The solid was collected by filtration and dried under aeration to provide the titled compound as pale yellow powder (111.1 mg, 62.0%).

Workup

  1. customThe reaction mixture was partitioned
  2. additionafter addition of ethyl acetate (50 ml)
  3. washThe separated organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (30 ml) and brine (30 ml)
  4. dry with materialdried over anhydrous sodium sulfate
  5. customThe solvent was removed under reduced pressure
  6. customThe resultant residue was purified by silica gel column chromatography (eluent
  7. additionFractions containing the target compound
  8. concentrationwere concentrated under reduced pressure
  9. additionto the residue (133.0 mg) were added tert-butyl methyl ether (4 ml) and heptane (4 ml)
  10. filtrationThe solid was collected by filtration
  11. customdried under aeration

Sources & evidence

ORD record
ord-6f9fd8f298504a559cd17bf08290e41e
Source dataset
uspto-grants-2012_10
Patent number
US08288538B2

Reaction notes

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