Dimethylformamide → N-(4-Fluorophenyl)-N'-(3-fluoro-4-{2-[(pyrrolidine-1-carbonyl)amino]pyridin-4-yloxy}phenyl)malonamide

HRID 492812Notes

Reaction equation

HRID 492812 reaction equation
[NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:23])[CH:3]=1.C(N(CC)CC)C.[F:31][P-](F)(F)(F)(F)F.[N:38]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2N=N1.C([O:60][CH2:61][CH3:62])C.CCCCCC.CN(C)[CH:71]=[O:72]>>[F:31][C:45]1[CH:44]=[CH:43][C:42]([NH:38][C:61](=[O:60])[CH2:62][C:71]([NH:1][C:2]2[CH:22]=[CH:21][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]4[CH2:17][CH2:18][CH2:19][CH2:20]4)=[O:15])[CH:8]=3)=[C:4]([F:23])[CH:3]=2)=[O:72])=[CH:41][CH:46]=1

Participants

6

Reactant 5

HCID 6228DimethylformamideHCID 8471TriethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 21584099Diethylether hexaneHCID 231530584-(4-Amino-2-fluorophenoxy)-2-[(pyrrolidin-1-yl)carbonylamino]pyridine

Product 1

HCID 23153094N-(4-Fluorophenyl)-N'-(3-fluoro-4-{2-[(pyrrolidine-1-carbonyl)amino]pyridin-4-yloxy}phenyl)malonamideYield 38.4%

Procedure

4-(4-Amino-2-fluorophenoxy)-2-[(pyrrolidin-1-yl)carbonylamino]pyridine (47.8 mg) was dissolved in N,N-dimethylformamide (2 ml) under a nitrogen atmosphere, and then N-(4-fluorophenyl)malonic acid (89.3 mg), triethylamine (0.063 ml) and (1H-1,2,3-benzotriazol-1-yloxy)[tri(dimethylamino)]phosphonium hexafluorophosphate (200 mg) were added thereto at 50° C., followed by stirring at the same temperature for 1 hr. The reaction mixture was cooled down to room temperature, followed by further stirring overnight. The reaction mixture was partitioned between ethyl acetate and a 1 N aqueous solution of sodium hydroxide. 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, then ethyl acetate:ethanol=95:5). Fractions containing the target compound were concentrated to give a residue, to which diethyl ether-hexane (1:1) was added to suspend. The solid was filtered off and dried under aeration to provide the titled compound (28.7 mg, 38.4%) as pale yellow powder.

Workup

  1. customat 50° C.
  2. stirringby further stirring overnight
  3. customThe reaction mixture was partitioned between ethyl acetate
  4. washThe organic layer was washed 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. customwas then purified by silica gel column chromatography (FUJI Silysia NH, eluent
  9. additionFractions containing the target compound
  10. concentrationwere concentrated
  11. customto give a residue
  12. filtrationThe solid was filtered off
  13. customdried under aeration

Sources & evidence

ORD record
ord-0331caf05db44e1ebd4fc21f82535e66
Source dataset
uspto-grants-2009_05
Patent number
US07531532B2

Reaction notes

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