2-(4-Fluorophenyl)acetic acid → 4-(2-Fluoro-4-{3-[2-(4-fluorophenyl)acetyl]thioureido}phenoxy)-2-[(pyrrolidin-1-yl)carbonylamino]pyridine

HRID 492776Notes

Reaction equation

HRID 492776 reaction equation
S(Cl)(Cl)=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=1.[S-:16][C:17]#[N:18].[K+].[NH2:20][C:21]1[CH:41]=[CH:40][C:24]([O:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]([N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[O:34])[CH:27]=2)=[C:23]([F:42])[CH:22]=1>C(#N)C.C(OCC)C>[F:42][C:23]1[CH:22]=[C:21]([NH:20][C:17]([NH:18][C:13](=[O:15])[CH2:12][C:9]2[CH:8]=[CH:7][C:6]([F:5])=[CH:11][CH:10]=2)=[S:16])[CH:41]=[CH:40][C:24]=1[O:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]([N:35]2[CH2:36][CH2:37][CH2:38][CH2:39]2)=[O:34])[CH:27]=1

Participants

7

Reactant 4

HCID 98372-(4-Fluorophenyl)acetic acidHCID 24386Thionyl ChlorideHCID 516872Potassium thiocyanateHCID 231530584-(4-Amino-2-fluorophenoxy)-2-[(pyrrolidin-1-yl)carbonylamino]pyridine

Product 1

HCID 113182154-(2-Fluoro-4-{3-[2-(4-fluorophenyl)acetyl]thioureido}phenoxy)-2-[(pyrrolidin-1-yl)carbonylamino]pyridineYield 54.4%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
50 °C

Procedure

Thionyl chloride (2.0 ml) was added to 2-(4-fluorophenyl)acetic acid (694 mg) under a nitrogen atmosphere, followed by stirring at 50° C. for 1 hr. The reaction mixture was concentrated under a reduced pressure to give a residue. The residue was dissolved in acetonitrile (100 ml) under a nitrogen atmosphere, and then potassium thiocyanate (875 mg) was added thereto at 50° C., followed by stirring at the same temperature for 2 hrs. The reaction mixture was cooled down to room temperature, and then 4-(4-amino-2-fluorophenoxy)-2-[(pyrrolidin-1-yl)carbonylamino]pyridine (949 mg) was added thereto, followed by stirring for 1 hr. The reaction mixture was concentrated under a reduced pressure to give a residue, which was then 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 under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:2 to 1:3). Fractions containing the target compound were concentrated to give a residue, to which diethyl ether (20 ml) was added to precipitate crystals. The crystals were filtered off and dried under aeration to provide the titled compound (834.5 mg, 54%) as white crystals.

Workup

  1. concentrationThe reaction mixture was concentrated under a reduced pressure
  2. customto give a residue
  3. customat 50° C.
  4. stirringby stirring at the same temperature for 2 hrs
  5. temperatureThe reaction mixture was cooled down to room temperature
  6. stirringby stirring for 1 hr
  7. concentrationThe reaction mixture was concentrated under a reduced pressure
  8. customto give a residue, which
  9. customwas then partitioned between ethyl acetate
  10. washThe organic layer was washed with brine
  11. dry with materialdried over anhydrous sodium sulfate
  12. customThe solvent was evaporated under a reduced pressure
  13. customto give a residue, which
  14. customwas then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:2 to 1:3)
  15. additionFractions containing the target compound
  16. concentrationwere concentrated
  17. customto give a residue
  18. customto precipitate crystals
  19. filtrationThe crystals were filtered off
  20. customdried under aeration

Sources & evidence

ORD record
ord-00e58ff84773497db325e1e4595318d4
Source dataset
uspto-grants-2009_05
Patent number
US07531532B2

Reaction notes

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