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 2265627Notes

Reaction equation

HRID 2265627 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-e2764df26b3044d0be2f3c420a1ae971
Source dataset
uspto-grants-2010_12
Patent number
US07855290B2

Reaction notes

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