Triethylamine → N-(3-Fluoro-4-{[2-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

HRID 2066201Notes

Reaction equation

HRID 2066201 reaction equation
[NH2:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:24])[N:15]([CH3:23])[CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH:8]=2)=[C:4]([F:27])[CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([C:38]2([C:41](O)=[O:42])[CH2:40][CH2:39]2)=[O:37])=[CH:31][CH:30]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[F:27][C:4]1[CH:3]=[C:2]([NH:1][C:41]([C:38]2([C:36]([NH:35][C:32]3[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=3)=[O:37])[CH2:40][CH2:39]2)=[O:42])[CH:26]=[CH:25][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:15]([CH3:23])[CH:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)=[O:24])[CH:8]=1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 210815301-[(4-Fluorophenyl)carbamoyl]cyclopropanecarboxylic AcidHCID 231535663-[4-(4-Amino-2-fluorophenoxy)pyridin-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea

Product 1

HCID 59596907N-(3-Fluoro-4-{[2-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideYield 42%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

3-[4-(4-Amino-2-fluorophenoxy)pyridin-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea (40.8 mg) was dissolved in N,N-dimethylformamide (1.0 ml). 1-(4-Fluorophenylcarbamoyl)cyclopropanecarboxylic acid (73 mg), triethylamine (0.0456 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (145 mg) were added under a nitrogen atmosphere at room temperature and stirred for 3.5 hr. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was removed and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=97:3) to provide the titled compound as white powder (26.3 mg, 42%).

Workup

  1. customLiquid-liquid separation
  2. additionafter addition of ethyl acetate and water to the reaction mixture
  3. washThe organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine
  4. dry with materialdried over anhydrous sodium sulfate
  5. customThe solvent was removed
  6. customthe resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent

Sources & evidence

ORD record
ord-a02eeffb50e847bfbb7afb7b4bcd0cbb
Source dataset
uspto-grants-2012_10
Patent number
US08288538B2

Reaction notes

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