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

HRID 445488
Notes
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Reaction equation

HRID 445488 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
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

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-fluorophenyl)-amide (4-hydroxy-phenyl)-amide (6.98 g, 22.2 mmol) in anhydrous 2,6-lutidine (50 mL) was added trifluoromethanesulfonic acid 6,7-dimethoxy-quinolin-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-4e3ff768c4f74676851e3984461eee17
Source dataset
uspto-grants-2013_07
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08476298B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes