Triethylamine → 3-[4-(3-Fluoro-4-{3-[2-(4-fluorophenyl)acetyl]thioureido}phenoxy)pyridin-2-yl]-1,1-dimethylurea

HRID 492794Notes

Reaction equation

HRID 492794 reaction equation
[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19](=[O:28])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[S:17])=[C:11]([F:29])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:30]([N:32]([CH2:35]C)[CH2:33]C)C.ClC(OC1C=CC=CC=1)=[O:39].Cl.CNC>O1CCCC1.CN(C)C=O.C(OCC)(=O)C.O>[F:29][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[NH:15][C:16]([NH:18][C:19](=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[S:17])[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:30](=[O:39])[N:32]([CH3:35])[CH3:33])[CH:7]=1

Participants

9

Reactant 4

HCID 8471Triethylamine2×HCID 10473Dimethylamine, hydrochlorideHCID 15891Phenyl chloroformateHCID 231534101-[4-(2-Aminopyridin-4-yloxy)-2-fluorophenyl]-3-[2-(4-fluorophenyl)acetyl]thiourea

Product 1

HCID 576775293-[4-(3-Fluoro-4-{3-[2-(4-fluorophenyl)acetyl]thioureido}phenoxy)pyridin-2-yl]-1,1-dimethylurea

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 1-[4-(2-aminopyridin-4-yloxy)-2-fluorophenyl]-3-[2-(4-fluorophenyl)acetyl]thiourea (26 mg) in tetrahydrofuran (2.0 ml) were added triethylamine (0.0175 ml) and phenyl chloroformate (0.0118 ml) in this order under a nitrogen atmosphere, followed by stirring at room temperature for 10 min. The solution was concentrated under a reduced pressure to give a residue, which was then dissolved in N,N-dimethylformamide (1.0 ml). Triethylamine (0.0873 ml) and dimethylamine hydrochloride (25.6 mg) were then added thereto, followed by stirring at room temperature for 24 hrs. To the reaction mixture was added water (30 ml) and ethyl acetate (50 ml), followed by stirring at room temperature for 4 hrs. The organic layer was separated, washed with brine (30 ml), 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, heptane:ethyl acetate=1:2, ethyl acetate, then ethyl acetate:methanol=20:1). Fractions containing the target compound were concentrated to give a residue, which was purified again by silica gel column chromatography (eluent; heptane:ethyl acetate=1:2, ethyl acetate, then ethyl acetate:methanol=20:1). Fractions containing the target compound were concentrated to give a pale yellow solid (83.7 mg), which was suspended in ethyl acetate (1 ml) and hexane (3 ml). The solid was filtered off and dried under aeration to provide the titled compound (4.8 mg, 15.8%) as colorless powder.

Workup

  1. concentrationThe solution was concentrated under a reduced pressure
  2. customto give a residue, which
  3. stirringby stirring at room temperature for 24 hrs
  4. stirringby stirring at room temperature for 4 hrs
  5. customThe organic layer was separated
  6. washwashed with brine (30 ml)
  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, heptane
  11. additionFractions containing the target compound
  12. concentrationwere concentrated
  13. customto give a residue, which
  14. customwas purified again by silica gel column chromatography (eluent
  15. additionFractions containing the target compound
  16. concentrationwere concentrated

Sources & evidence

ORD record
ord-bc7a6b1db17a408b9ed49b6228b336d9
Source dataset
uspto-grants-2009_05
Patent number
US07531532B2

Reaction notes

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