Benzeneacetamide → 4-{2-Fluoro-4-[3-(2-phenylacetyl)ureido]phenoxy}-2-{[4-(pyrrolidin-1-yl)piperidin-1-yl]carbonylamino}pyridine

HRID 492804Notes

Reaction equation

HRID 492804 reaction equation
[C:1]1([CH2:7][C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)[C:12](Cl)=[O:13].[NH2:17][C:18]1[CH:44]=[CH:43][C:21]([O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]([N:32]3[CH2:37][CH2:36][CH:35]([N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)[CH2:34][CH2:33]3)=[O:31])[CH:24]=2)=[C:20]([F:45])[CH:19]=1>ClCCCl.CN(C)C=O.C(OCC)(=O)C>[F:45][C:20]1[CH:19]=[C:18]([NH:17][C:12]([NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:13])[CH:44]=[CH:43][C:21]=1[O:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]([N:32]2[CH2:37][CH2:36][CH:35]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:34][CH2:33]2)=[O:31])[CH:24]=1

Participants

7

Reactant 3

HCID 7680BenzeneacetamideHCID 65578Oxalyl chlorideHCID 231534244-(4-Amino-2-fluorophenoxy)-2-{[4-(pyrrolidin-1-yl)piperidin-1-yl]carbonylamino}pyridine

Product 1

HCID 231536254-{2-Fluoro-4-[3-(2-phenylacetyl)ureido]phenoxy}-2-{[4-(pyrrolidin-1-yl)piperidin-1-yl]carbonylamino}pyridineYield 28%

Reagents, catalysts & solvents 3

HCID 111,2-DichloroethaneSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
120 °C

Procedure

2-Phenylacetamide (203 mg) was dissolved in 1,2-dichloroethane (20 ml) under a nitrogen atmosphere, and then oxalyl chloride (0.174 ml) was added thereto, followed by stirring at 120° C. overnight. The reaction mixture was concentrated under a reduced pressure to give a residue, which was then dissolved in N,N-dimethylformamide (5 ml) under a nitrogen atmosphere. 4-(4-Amino-2-fluorophenoxy)-2-{[4-(pyrrolidin-1-yl)piperidin-1-yl]carbonylamino}pyridine (295 mg) was then added thereto, followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with 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:methanol=98:2). Fractions containing the target compound were concentrated under a reduced pressure to give a brown powder residue, which was then dissolved in ethyl acetate (10 ml) to extract with 1 N hydrochloric acid (5 ml). To the aqueous layer was added a 1 N aqueous solution of sodium hydroxide dropwise to make it neutral, followed by stirring overnight. The precipitated solid was filtered off, washed with water, and dried under aeration at 60° C. to provide the titled compound (116 mg, 28%) as pale pink powder.

Workup

  1. concentrationThe reaction mixture was concentrated under a reduced pressure
  2. customto give a residue, which
  3. stirringby stirring for 1 hr
  4. customThe reaction mixture was partitioned between ethyl acetate
  5. washThe organic layer was washed with water and brine in this order
  6. dry with materialdried over anhydrous sodium sulfate
  7. customThe solvent was evaporated
  8. customto give a residue, which
  9. customwas then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate:methanol=98:2)
  10. additionFractions containing the target compound
  11. concentrationwere concentrated under a reduced pressure
  12. customto give a brown powder residue, which
  13. extractionto extract with 1 N hydrochloric acid (5 ml)
  14. additionTo the aqueous layer was added a 1 N aqueous solution of sodium hydroxide dropwise
  15. stirringby stirring overnight
  16. filtrationThe precipitated solid was filtered off
  17. washwashed with water
  18. customdried under aeration at 60° C.

Sources & evidence

ORD record
ord-6b8490d320074dae9262e575035fe20e
Source dataset
uspto-grants-2009_05
Patent number
US07531532B2

Reaction notes

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