Trifluoromethanesulfonic acid 6,7-dimethoxyquinolin-4-yl ester → Cabozantinib

HRID 705646Notes

Reaction equation

HRID 705646 reaction equation
[OH: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]([F:23])=[CH:19][CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][CH3:37])[N:32]=[CH:31][CH:30]=[C:29]2OS(C(F)(F)F)(=O)=O>N1C(C)=CC=CC=1C>[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][CH3:37])[N:32]=[CH:31][CH:30]=[C:29]2[O: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:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1

Participants

4

Reactant 2

HCID 18788711Trifluoromethanesulfonic acid 6,7-dimethoxyquinolin-4-yl esterHCID 57810197N-(4-Fluorophenyl)-N'-(4-hydroxyphenyl)cyclopropane-1,1-dicarboxamide

Product 1

HCID 25102847CabozantinibYield 44%

Reagents, catalysts & solvents 1

HCID 79372,6-LutidineSolvent

Conditions

Temperature
165 °C

Procedure

To a solution of cyclopropane-1,1-dicarboxylic acid (4-fluoro-phenyl)-amide (4-hydroxy-phenyl)-amide (6.98 g, 22.2 mmol) in anhydrous 2,6-lutidine (50 mL) was added trifluoromethanesulfonic acid 6,7-dimethoxyquinolin-4-yl ester (5 g, 14.8 mmol). The reaction mixture was heated at 165° C. in a sealed pressure tube with stirring for 18 h. The reaction mixture was concentrated on high vacuum to completely remove lutidine. The resulting solid material was dissolved in DCM (250 mL), and washed several times with 1 N sodium hydroxide to remove the excess phenol. The crude mixture was loaded on a silica gel flash column and eluted with 75% EtOAc-hexanes, affording N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4 fluorophenyl)cyclopropane-1,1-dicarboxamide (3.2 g, 44%). 1H NMR (400 MHz, d6-DMSO): δ 10.2 (s, 1H), 10.05 (s, 1H), 8.4 (s, 1H), 7.8 (m, 2H), 7.65 (m, 2H), 7.5 (s, 1H), 7.35 (s, 1H), 7.25 (m, 2H), 7.15 (m, 2H), 6.4 (s, 1H), 4.0 (d, 6H), 1.5 (s, 4H). LC/MS: M+H=502.

Workup

  1. concentrationThe reaction mixture was concentrated on high vacuum to completely remove lutidine
  2. dissolutionThe resulting solid material was dissolved in DCM (250 mL)
  3. washwashed several times with 1 N sodium hydroxide
  4. customto remove the excess phenol
  5. washeluted with 75% EtOAc-hexanes

Sources & evidence

ORD record
ord-2350bdfccd3f481680766dc737497a04
Source dataset
uspto-grants-2015_11
Patent number
US09174947B2

Reaction notes

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