Diethyl Ether → N-(2-Chloro-4-{2-[(pyrrolidine-1-carbonyl)amino]pyridin-4-yloxy}phenyl)-N'-(4-fluorophenyl)malonamide

HRID 492816Notes

Reaction equation

HRID 492816 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)=[CH:4][C:3]=1[Cl:23].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.CN(C)[CH:65]=[O:66]>CCCCCC>[Cl:23][C:3]1[CH:4]=[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)[CH:21]=[CH:22][C:2]=1[NH:1][C:61](=[O:60])[CH2:62][C:65]([NH:38][C:42]1[CH:43]=[CH:44][C:45]([F:31])=[CH:46][CH:41]=1)=[O:66]

Participants

7

Reactant 5

HCID 3283Diethyl EtherHCID 6228DimethylformamideHCID 8471TriethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 231535334-(4-Amino-3-chlorophenoxy)-2-[(pyrrolidin-1-yl)carbonylamino]pyridine

Product 1

HCID 23153002N-(2-Chloro-4-{2-[(pyrrolidine-1-carbonyl)amino]pyridin-4-yloxy}phenyl)-N'-(4-fluorophenyl)malonamideYield 76.9%

Reagents, catalysts & solvents 1

HCID 8058HexaneSolvent

Procedure

Pyrrolidine-1-carboxylic acid [4-(4-amino-3-chlorophenoxy)pyridin-2-yl]amide (79.6 mg) was dissolved in N,N-dimethylformamide (1.5 ml) under a nitrogen atmosphere, and then N-(4-fluorophenyl)malonic acid (142 mg), triethylamine (0.100 ml), and (1H-1,2,3-benzotriazol-1-yloxy)[tri(dimethylamino)]phosphonium hexafluorophosphate (318 mg) were added thereto at 50° C., followed by stirring at the same temperature for 2 hrs and 30 min. The reaction mixture was cooled down to room temperature, and 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 (eluent; ethyl acetate). Fractions containing the target compound were concentrated to give a residue, to which diethyl ether (5 ml)-hexane (5 ml) was added to suspend. The solid was filtered off and dried under aeration to provide the titled compound (94.5 mg, 76.9%) as white powder.

Workup

  1. customat 50° C.
  2. custompartitioned between ethyl acetate
  3. washThe organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order
  4. dry with materialdried over anhydrous sodium sulfate
  5. customThe solvent was evaporated
  6. customto give a residue, which
  7. customwas then purified by silica gel column chromatography (eluent; ethyl acetate)
  8. additionFractions containing the target compound
  9. concentrationwere concentrated
  10. customto give a residue
  11. filtrationThe solid was filtered off
  12. customdried under aeration

Sources & evidence

ORD record
ord-1fff58b19af345919e67e94804a110ab
Source dataset
uspto-grants-2009_05
Patent number
US07531532B2

Reaction notes

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