Phenylacetyl chloride → 3-{4-[2-Fluoro-4-(3-phenylacetylthioureido)phenoxy]pyridin-2-yl}-1-methyl-1-(1-methylpiperidin-4-yl)urea

HRID 492790Notes

Reaction equation

HRID 492790 reaction equation
C1(CC(Cl)=O)C=CC=CC=1.[S-]C#N.[K+].C(=O)([O-])O.[Na+].[NH2:20][C:21]1[CH:45]=[CH:44][C:24]([O:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33](=[O:43])[N:34]([CH3:42])[CH:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)[CH:27]=2)=[C:23]([F:46])[CH:22]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[C:62]1([CH2:68][C:69]([N:71]=[C:72]=[S:73])=[O:70])[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>C(#N)C.C(O)C.C1(C)C(CCO)=CC=CC=1.CCCCCC.C(OCC)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:46][C:23]1[CH:22]=[C:21]([NH:20][C:72]([NH:71][C:69](=[O:70])[CH2:68][C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)=[S:73])[CH:45]=[CH:44][C:24]=1[O:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33](=[O:43])[N:34]([CH3:42])[CH:35]2[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]2)[CH:27]=1

Participants

14

Reactant 6

HCID 7679Phenylacetyl chlorideHCID 18462Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S)-HCID 516872Potassium thiocyanateHCID 516892Sodium BicarbonateHCID 12454157Phenylacetyl isothiocyanateHCID 231535663-[4-(4-Amino-2-fluorophenoxy)pyridin-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea

Product 1

HCID 576776833-{4-[2-Fluoro-4-(3-phenylacetylthioureido)phenoxy]pyridin-2-yl}-1-methyl-1-(1-methylpiperidin-4-yl)ureaYield 17.5%

Reagents, catalysts & solvents 7

HCID 702EthanolSolvent2×HCID 1140TolueneSolventHCID 3283Diethyl EtherSolventHCID 6342AcetonitrileSolventHCID 8058HexaneSolventHCID 8857Ethyl AcetateSolventHCID 882672-Methylphenethyl alcoholSolvent

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, to which was added toluene (1 ml)-ethanol (1 ml) to prepare a solution. 3-[4-(4-Amino-2-fluorophenoxy)pyridin-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea (40.0 mg) was dissolved in ethanol (1 ml) under a nitrogen atmosphere, and then D-10-camphorsulfonic acid (24.9 mg) was added thereto, followed by stirring for 5 min. To the reaction mixture was added the solution of 2-phenylacetyl isothiocyanate in toluene-ethanol (2 ml) synthesized above, followed by stirring at room temperature for 30 min. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was 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 purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated to give a residue, to which diethyl ether (0.5 ml)-hexane (1.0 ml) was then added to suspend. The solid was filtered off and dried under aeration to provide the titled compound (10.3 mg, 17.5%) 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
  8. customto prepare a solution
  9. stirringby stirring for 5 min
  10. customsynthesized above,
  11. stirringby stirring at room temperature for 30 min
  12. customThe reaction mixture was partitioned between ethyl acetate
  13. washThe organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order
  14. dry with materialdried over anhydrous sodium sulfate
  15. customThe solvent was evaporated
  16. customto give a residue, which
  17. customwas then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate)
  18. additionFractions containing the target compound
  19. concentrationwere concentrated
  20. customto give a residue
  21. filtrationThe solid was filtered off
  22. customdried under aeration

Sources & evidence

ORD record
ord-bb29c431ddf54d9e8699a5f88afeed01
Source dataset
uspto-grants-2009_05
Patent number
US07531532B2

Reaction notes

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