Triethylamine → N-(4-Fluorophenyl)-N'-(4-{[2-({[4-(pyrrolidin-1-ylmethyl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide

HRID 2265652Notes

Reaction equation

HRID 2265652 reaction equation
[NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38]([C:40]2([C:43](O)=[O:44])[CH2:42][CH2:41]2)=[O:39])=[CH:33][CH:32]=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:30][C:31]1[CH:32]=[CH:33][C:34]([NH:37][C:38]([C:40]2([C:43]([NH:1][C:2]3[CH:29]=[CH:28][C:5]([O:6][C:7]4[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]5[CH2:17][CH2:18][CH:19]([CH2:22][N:23]6[CH2:27][CH2:26][CH2:25][CH2:24]6)[CH2:20][CH2:21]5)=[O:15])[CH:8]=4)=[CH:4][CH:3]=3)=[O:44])[CH2:42][CH2:41]2)=[O:39])=[CH:35][CH:36]=1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 210815301-[(4-Fluorophenyl)carbamoyl]cyclopropanecarboxylic AcidHCID 59596970N-[4-(4-aminophenoxy)-2-pyridinyl]-4-(1-pyrrolidinylmethyl)-1-piperidinecarboxamide

Product 1

HCID 59596909N-(4-Fluorophenyl)-N'-(4-{[2-({[4-(pyrrolidin-1-ylmethyl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamideYield 63.8%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

4-(Pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide (125 mg) was dissolved in N,N-dimethylformamide (2 ml), and 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (176 mg), triethylamine (0.11 ml) and (1H-1,2,3-benzotriazol-1-yloxy)[tri(dimethylamino)]phosphonium hexafluorophosphate (349 mg) were added thereto in this order at room temperature, followed by stirring for 1 hr. Liquid-liquid separation was carried out after addition of ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate to the reaction mixture. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:5, then ethyl acetate). The solvent was concentrated under reduced pressure, and the resultant residue was suspended in diethyl ether (4 ml) and hexane (4 ml). The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (121.2 mg, 63.8%).

Workup

  1. customat room temperature
  2. customLiquid-liquid separation
  3. additionafter addition of ethyl acetate
  4. washThe organic layer was washed with brine
  5. dry with materialdried over anhydrous sodium sulfate
  6. concentrationThe solvent was concentrated under reduced pressure
  7. customthe resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent
  8. concentrationThe solvent was concentrated under reduced pressure
  9. filtrationThe solid was collected by filtration
  10. customdried under aeration

Sources & evidence

ORD record
ord-7f4fdf7dfcc240498784a84088b8b5bd
Source dataset
uspto-grants-2010_12
Patent number
US07855290B2

Reaction notes

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