Diethyl Ether → N-(2-Fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridin-4-yloxy}phenyl)-N'-(4-fluorophenyl)malonamide

HRID 492829Notes

Reaction equation

HRID 492829 reaction equation
[CH3:1][N:2](C)[CH:3]=[O:4].C([O:8][CH2:9][CH3:10])C.[NH2:11][C:12]1[CH:36]=[CH:35][C:15]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:34])[N:25]([CH3:33])[CH:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[CH:18]=2)=[CH:14][C:13]=1[F:37]>>[F:37][C:13]1[CH:14]=[C:15]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]([N:25]([CH3:33])[CH:26]3[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]3)=[O:34])[CH:18]=2)[CH:35]=[CH:36][C:12]=1[NH:11][C:9](=[O:8])[CH2:10][C:3]([NH:2][C:1]1[CH:15]=[CH:14][C:13]([F:37])=[CH:12][CH:36]=1)=[O:4]

Participants

4

Reactant 3

HCID 3283Diethyl EtherHCID 6228DimethylformamideHCID 231531123-[4-(4-Amino-3-fluorophenoxy)pyridin-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea2×

Product 1

HCID 23153521N-(2-Fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridin-4-yloxy}phenyl)-N'-(4-fluorophenyl)malonamideYield 48.8%

Procedure

To a solution of 3-[4-(4-amino-3-fluorophenoxy)pyridin-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea (40.5 mg) in tetrahydrofuran (20 ml) (Production Example 124) was added N,N-dimethylformamide (2 ml) under a nitrogen atmosphere, followed by evaporating the tetrahydrofuran under a reduced pressure. To the solution thus concentrated were added N-(4-fluorophenyl)malonic acid (42.6 mg), triethylamine (0.030 ml) and (1H-1,2,3-benzotriazol-1-yloxy)[tri(dimethylamino)]phosphonium hexafluorophosphate (95.5 mg) at room temperature, followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate (30 ml) and a saturated aqueous solution of ammonium chloride (15 ml). The organic layer was washed with a saturated aqueous solution of ammonium chloride (15 ml), water (15 ml) and brine (15 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate-ethyl acetate:ethanol=95:5). Fractions containing the target compound were concentrated to give a residue, to which diethyl ether (1 ml) was added to suspend. The solid was filtered off and dried under aeration to provide the titled compound (29.1 mg, 48.8%) as a pale green and yellow solid.

Workup

  1. customby evaporating the tetrahydrofuran under a reduced pressure
  2. concentrationTo the solution thus concentrated
  3. additionwere added N-(4-fluorophenyl)malonic acid (42.6 mg), triethylamine (0.030 ml) and (1H-1,2,3-benzotriazol-1-yloxy)[tri(dimethylamino)]phosphonium hexafluorophosphate (95.5 mg) at room temperature
  4. customThe reaction mixture was partitioned between ethyl acetate (30 ml)
  5. washThe organic layer was washed with a saturated aqueous solution of ammonium chloride (15 ml), water (15 ml) and brine (15 ml) in this order
  6. dry with materialdried over anhydrous sodium sulfate
  7. customThe solvent was evaporated
  8. customto give a residue, which
  9. customwas then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate-ethyl acetate:ethanol=95:5)
  10. additionFractions containing the target compound
  11. concentrationwere concentrated
  12. customto give a residue
  13. filtrationThe solid was filtered off
  14. customdried under aeration

Sources & evidence

ORD record
ord-f32d3752db7146dc87456dfd1b5c5bff
Source dataset
uspto-grants-2009_05
Patent number
US07531532B2

Reaction notes

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