2-(4-Fluorophenyl)acetyl isocyanate → 2-{[4-(Azetidin-1-yl)piperidin-1-yl]carbonylamino}-4-(4-{3-[2-(4-fluorophenyl)acetyl]ureido}phenoxy)pyridine

HRID 492944Notes

Reaction equation

HRID 492944 reaction equation
[NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:25][CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([N:38]=[C:39]=[O:40])=[O:37])=[CH:31][CH:30]=1>O1CCCC1.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>[N:22]1([CH:19]2[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]3[CH:8]=[C:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:39]([NH:38][C:36](=[O:37])[CH2:35][C:32]5[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=5)=[O:40])=[CH:27][CH:26]=4)[CH:12]=[CH:11][N:10]=3)=[O:15])[CH2:21][CH2:20]2)[CH2:25][CH2:24][CH2:23]1

Participants

6

Reactant 2

HCID 231530882-(4-Fluorophenyl)acetyl isocyanate3×HCID 231534034-(4-Aminophenoxy)-2-{[4-(azetidin-1-yl)piperidin-1-yl]carbonylamino}pyridine

Product 1

HCID 231531562-{[4-(Azetidin-1-yl)piperidin-1-yl]carbonylamino}-4-(4-{3-[2-(4-fluorophenyl)acetyl]ureido}phenoxy)pyridineYield 17%

Reagents, catalysts & solvents 3

HCID 8028TetrahydrofuranSolvent4×HCID 8857Ethyl AcetateSolventHCID 81531DiisopropylethylamineSolvent

Procedure

To a solution of 4-(4-aminophenoxy)-2-{[4-(azetidin-1-yl)piperidin-1-yl]carbonylamino}pyridine (67.8 mg) in tetrahydrofuran (2.5 ml) was added a solution of 2-(4-fluorophenyl)acetyl isocyanate in tetrahydrofuran (0.25 M, 2.2 ml) at room temperature, followed by stirring for 2 hours. A solution of 2-(4-fluorophenyl)acetyl isocyanate in tetrahydrofuran (0.25 M, 1.5 ml) was further added thereto at room temperature. After 6 hours, a solution of 2-(4-fluorophenyl)acetyl isocyanate in tetrahydrofuran (0.25 M, 1.85 ml) and diisopropylethylamine (0.322 ml) were added thereto at room temperature, followed by stirring for 2 days. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine 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, then ethyl acetate:methanol=97:3). Fractions containing the target compound were concentrated to give a residue, which was then suspended in ethyl acetate (1 ml). The solid was filtered off and dried under aeration to provide the titled compound (17.0 mg, 17%) as white powder.

Workup

  1. customat room temperature
  2. waitAfter 6 hours
  3. customat room temperature
  4. stirringby stirring for 2 days
  5. customThe reaction mixture was partitioned between ethyl acetate
  6. washThe organic layer was washed with brine
  7. dry with materialdried over anhydrous sodium sulfate
  8. customThe solvent was evaporated
  9. customto give a residue, which
  10. customwas then purified by silica gel column chromatography (Fuji Silysia NH, eluent
  11. additionFractions containing the target compound
  12. concentrationwere concentrated
  13. customto give a residue, which
  14. filtrationThe solid was filtered off
  15. customdried under aeration

Sources & evidence

ORD record
ord-e8a284f4bebd464db102e5e842ca43ae
Source dataset
uspto-grants-2009_05
Patent number
US07531532B2

Reaction notes

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