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

HRID 445482
Notizen
Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 445482
[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
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Komponenten

4

Edukt 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

Produkt 1

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

Reaktionsbedingungen

Temperatur
143 °C

Versuchsvorschrift

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.

Aufarbeitung

  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)

Quellen und Nachweise

ORD-Eintrag
ord-257c6ae305d245508a8a11e13140d707
Quelldatensatz
uspto-grants-2013_07
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US08476298B2

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