Water → N-(4-{[6,7-bis(methyloxy)-2-(methylthio)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-(4-fluoro-phenyl)cyclopropane-1,1-dicarboxamide

HRID 2106160Notes

Reaction equation

HRID 2106160 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([S:15][CH3:16])[CH:7]=[C:6]2[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=1[F:25].[F:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]2([C:39](O)=[O:40])[CH2:38][CH2:37]2)=[O:35])=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([S:15][CH3:16])[CH:7]=[C:6]2[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:39]([C:36]2([C:34]([NH:33][C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)=[O:35])[CH2:38][CH2:37]2)=[O:40])=[CH:20][C:19]=1[F:25]

Participants

6

Reactant 4

HCID 962WaterHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 210815301-[(4-Fluorophenyl)carbamoyl]cyclopropanecarboxylic AcidHCID 578100734-(6,7-Dimethoxy-2-methylsulfanyl-quinolin-4-yloxy)-3-fluorophenylamine

Product 1

HCID 57810395N-(4-{[6,7-bis(methyloxy)-2-(methylthio)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-(4-fluoro-phenyl)cyclopropane-1,1-dicarboxamideYield 113%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a mixture of 4-(6,7-dimethoxy-2-methylsulfanyl-quinolin-4-yloxy)-3-fluoro-phenylamine (0.22 g, 0.61 mmol) and 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (0.16 g, 0.73 mmol) in DMF (5 mL) was added TEA (0.25 mL, 1.8 mmol) followed by HATU (0.57 g, 1.5 mmol). The resulting solution was stirred overnight at room temperature. The reaction mixture was dumped into water and extracted with DCM (2×). The combined extracts were washed with 5% LiCl(aq) (3×), water, (1×) and brine (1×), followed by drying over Na2SO4 and concentration in vacuo. The crude solids were purified by preparatory HPLC with ammonium acetate, affording N-(4-{[6,7-bis(methyloxy)-2-(methylthio)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (0.39 g, 11% yield) as a white solid. 1H NMR (DMSO-d6) δ 10.34 (s, 1H), 9.94 (s, 1H), 7.83 (d, 1H), 7.59 (m, 2H), 7.56 (m, 1H), 7.40 (m, 2H), 7.23 (s, 1H), 7.09 (t, 2H), 6.12 (s, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 2.48 (s, 3H), 1.40 (m, 4H).

Workup

  1. extractionextracted with DCM (2×)
  2. washThe combined extracts were washed with 5% LiCl(aq) (3×), water, (1×) and brine (1×)
  3. dry with materialby drying over Na2SO4 and concentration in vacuo
  4. customThe crude solids were purified by preparatory HPLC with ammonium acetate

Sources & evidence

ORD record
ord-868e55083a094f4882969b07ed786123
Source dataset
uspto-grants-2009_08
Patent number
US07579473B2

Reaction notes

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