2,6-Lutidine → N-[3-Fluoro-4-[[6-methoxy-7-(phenylmethoxy)-4-quinolinyl]oxy]phenyl]-N'-(4-fluorophenyl)-1,1-cyclopropanedicarboxamide

HRID 563002Notes

Reaction equation

HRID 563002 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([F:24])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH2:25]([O:32][C:33]1[CH:42]=[C:41]2[C:36]([C:37](OS(C(F)(F)F)(=O)=O)=[CH:38][CH:39]=[N:40]2)=[CH:35][C:34]=1[O:51][CH3:52])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.N1C(C)=CC=CC=1C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:37]4[C:36]5[C:41](=[CH:42][C:33]([O:32][CH2:25][C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)=[C:34]([O:51][CH3:52])[CH:35]=5)[N:40]=[CH:39][CH:38]=4)=[C:19]([F:24])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:6][CH:7]=1

Participants

4

Reactant 3

HCID 79372,6-LutidineHCID 46899431N-(3-Fluoro-4-hydroxyphenyl)-N'-(4-fluorophenyl)-1,1-cyclopropanedicarboxamideHCID 57810077Trifluoromethanesulfonic acid 7-benzyloxy-6-methoxy-quinolin-4-yl ester

Product 1

HCID 57810139N-[3-Fluoro-4-[[6-methoxy-7-(phenylmethoxy)-4-quinolinyl]oxy]phenyl]-N'-(4-fluorophenyl)-1,1-cyclopropanedicarboxamideYield 48%

Conditions

Temperature
143 °C

Procedure

To a flask containing cyclopropane-1,1-dicarboxylic acid (3-fluoro-4-hydroxy-phenyl)-amide (4-fluoro-phenyl)-amide (2.25 g, 6.7 mmol) and trifluoromethanesulfonic acid 7-benzyloxy-6-methoxy-quinolin-4-yl ester (1.87 g, 4.5 mmol) was added dry 2,6-lutidine (9 mL). The reaction mixture was heated to reflux (143° C.) with vigorous stirring. The reaction progress was monitored by LC-MS. 2,6-Lutidine was removed under reduced pressure when the reaction was complete (about 6 h). The residue was treated with charcoal (1.5 g) in refluxing EtOAc (50 mL) for 15 min, and filtered through celite. The volume of the filtrate was reduced to about 20 mL and was added 20 mL of 1 N HCl. The crude product precipitated as the HCl salt, which was filtered and washed with EtOAc and H2O (88% purity by analytical HPLC). The HCl salt was free-based with saturated aqueous NaHCO3 solution. Further purification by column chromatography (hexans:EtOAc=1:4) gave cyclopropane-1,1-dicarboxylic acid [4-(7-benzyloxy-6-methoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide (4-fluoro-phenyl)-amide as an off-white solid (1.3 g, 48% yield. 1H NMR (400 MHz, DMSO, d6): 10.41 (s, 1H), 10.02 (s, 1H), 8.48 (d, 1H), 7.92 (dd, 1H), 7.65 (m, 2H), 7.54 (m, 5H), 7.41 (m, 4H), 7.17 (m, 2H), 6.43 (d, 1H), 5.32 (s, 2H), 3.97 (s, 3H), 1.48 (m, 4H). LC/MS Calcd for [M+H]+ 596.2, found 596.3.

Workup

  1. temperatureThe reaction mixture was heated
  2. custom2,6-Lutidine was removed under reduced pressure when the reaction
  3. custom(about 6 h)
  4. additionThe residue was treated with charcoal (1.5 g)
  5. temperaturein refluxing EtOAc (50 mL) for 15 min
  6. filtrationfiltered through celite
  7. additionwas added 20 mL of 1 N HCl
  8. customThe crude product precipitated as the HCl salt, which
  9. filtrationwas filtered
  10. washwashed with EtOAc and H2O (88% purity by analytical HPLC)
  11. customFurther purification by column chromatography (hexans:EtOAc=1:4)

Sources & evidence

ORD record
ord-05bb483f0aac4b3b99e875d3c1007164
Source dataset
uspto-grants-2011_11
Patent number
US08067436B2

Reaction notes

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