Phenylacetyl chloride → 1-(3-Dimethylaminopropyl)-3-{6-[2-fluoro-4-(3-phenylacetylthioureido)phenoxy]pyrimidin-4-yl}-1-methylurea

HRID 492789Notes

Reaction equation

HRID 492789 reaction equation
[C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-:11][C:12]#[N:13].[K+].C(=O)([O-])O.[Na+].[NH2:20][C:21]1[CH:46]=[CH:45][C:24]([O:25][C:26]2[N:31]=[CH:30][N:29]=[C:28]([NH:32][C:33](=[O:44])[N:34]([CH2:36][CH2:37][CH2:38][N:39]([CH2:42]C)[CH2:40]C)[CH3:35])[CH:27]=2)=[C:23]([F:47])[CH:22]=1>C(#N)C.C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C>[CH3:40][N:39]([CH3:42])[CH2:38][CH2:37][CH2:36][N:34]([CH3:35])[C:33]([NH:32][C:28]1[CH:27]=[C:26]([O:25][C:24]2[CH:45]=[CH:46][C:21]([NH:20][C:12]([NH:13][C:8](=[O:9])[CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[S:11])=[CH:22][C:23]=2[F:47])[N:31]=[CH:30][N:29]=1)=[O:44]

Participants

9

Reactant 4

HCID 7679Phenylacetyl chlorideHCID 516872Potassium thiocyanateHCID 516892Sodium BicarbonateHCID 231534393-[6-(4-Amino-2-fluorophenoxy)pyrimidin-4-yl]-1-(3-diethylaminopropyl)-1-methylurea

Product 1

HCID 866021641-(3-Dimethylaminopropyl)-3-{6-[2-fluoro-4-(3-phenylacetylthioureido)phenoxy]pyrimidin-4-yl}-1-methylureaYield 12.5%

Reagents, catalysts & solvents 4

HCID 702EthanolSolvent2×HCID 1140TolueneSolvent2×HCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Procedure

2-Phenylacetyl chloride (0.032 ml) was dissolved in acetonitrile (3 ml) under a nitrogen atmosphere, and then potassium thiocyanate (46.6 mg) was added thereto at 60° C., followed by stirring at the same temperature for 2 hrs. The reaction mixture was cooled down to room temperature, and then ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate were added thereto, followed by stirring for 30 min. The organic layer was separated, washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then dissolved in toluene (1 ml)-ethanol (1 ml), and then a solution of 3-[6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]-1-(3-diethylaminopropyl)-1-methylurea in toluene (1.5 ml)-ethanol (1.5 ml) was added thereto under a nitrogen atmosphere, followed by stirring at room temperature for 2 hrs. The reaction mixture was partitioned between ethyl acetate and water. 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; heptane:ethyl acetate=1:1). Fractions containing the crude product were concentrated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; heptane:ethyl acetate=1:1). Fractions containing the target compound were concentrated to give a residue, which was dried in vacuum to provide the titled compound (6.0 mg, 12.5%) as a white solid.

Workup

  1. customat 60° C.
  2. stirringby stirring for 30 min
  3. customThe organic layer was separated
  4. washwashed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order
  5. dry with materialdried over anhydrous sodium sulfate
  6. customThe solvent was evaporated
  7. customto give a residue, which
  8. stirringby stirring at room temperature for 2 hrs
  9. customThe reaction mixture was partitioned between ethyl acetate and water
  10. washThe organic layer was washed with brine
  11. dry with materialdried over anhydrous sodium sulfate
  12. customThe solvent was evaporated
  13. customto give a residue, which
  14. customwas then purified by silica gel column chromatography (FUJI Silysia NH, eluent; heptane:ethyl acetate=1:1)
  15. additionFractions containing the crude product
  16. concentrationwere concentrated
  17. customto give a residue, which
  18. customwas then purified by silica gel column chromatography (FUJI Silysia NH, eluent; heptane:ethyl acetate=1:1)
  19. additionFractions containing the target compound
  20. concentrationwere concentrated
  21. customto give a residue, which
  22. customwas dried in vacuum

Sources & evidence

ORD record
ord-f1acd540736c427ab49d96b7db10cea0
Source dataset
uspto-grants-2009_05
Patent number
US07531532B2

Reaction notes

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