4-Fluoroaniline → N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)-1-(phenylmethyl)azetidine-3,3-dicarboxamide

HRID 705682

Reaction equation

HRID 705682 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](OC1C=CC(N)=CC=1)[CH:7]=[CH:6]2.[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.CC[N:33]([CH:37]([CH3:39])[CH3:38])C(C)C.[CH2:40]([N:47]1[CH2:50][C:49]([C:54]([OH:56])=[O:55])([C:51]([OH:53])=[O:52])[CH2:48]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:40]([N:47]1[CH2:48][C:49]([C:51]([OH:53])=[O:52])([C:54]([OH:56])=[O:55])[CH2:50]1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1.[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]=[CH:8][CH:7]=[C:6]2[O:2][C:3]1[CH:4]=[CH:38][C:37]([NH:33][C:54]([C:49]2([C:51]([NH:28][C:27]3[CH:29]=[CH:30][C:24]([F:23])=[CH:25][CH:26]=3)=[O:53])[CH2:48][N:47]([CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH2:50]2)=[O:56])=[CH:39][CH:12]=1

Participants

8

Reactant 4

HCID 97314-FluoroanilineHCID 81531DiisopropylethylamineHCID 113108851-benzylazetidine-3,3-dicarboxylic AcidHCID 666663974-[(6,7-Dimethoxy-quinolyl)oxy]aniline

Product 2

HCID 113108851-benzylazetidine-3,3-dicarboxylic AcidHCID 57810238N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)-1-(phenylmethyl)azetidine-3,3-dicarboxamideYield 23.5%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

1-Benzyl-azetidine-3,3-dicarboxylic acid was prepared by following the literature procedure (Miller, R. A.; et al. Syn. Comm. 2003, 33, 3347). To a solution of 4-(6,7-dimethoxy-quinolinyloxy)-phenylamine (4.2 mmol, 1 equiv.) and 4-fluoroaniline (4.2 mmol, 1 equiv.) in DMF (20 mL) was charged with DIEA (12.6 mmol, 3 equiv.) and a solution of 1-benzyl-azetidine-3,3-dicarboxylic acid (4.2 mmol, 1 equiv.) in DMF (10 mL). The reaction mixture was allowed to stir at RT and monitored by LCMS. The reaction was complete in 6 h. The reaction mixture was diluted with ethyl acetate and washed with 10% LiCl (3×), brine (3×), dried with sodium sulfate, filtered and the solvent was reduced in vacuo. The crude product was purified by silica gel chromatography eluting with 2% of MeOH in EtOAc. The fractions containing the desired product were further purified using preparative HPLC to give ′N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)-1-(phenylmethyl)azetidine-3,3-dicarboxamide (300 mg, 12% yield) as a white solid. 1HNMR (DMSO-d6): 10.0 (s, 1H), 9.90 (s, 1H), 8.45 (d, 1H), 7.80 (d, 2H), 7.70 (m, 2H), 7.50 (s, 1H), 7.40 (s, 1H), 7.48-7.15 (m, 9H), 3.95 (s, 6H), 3.70 (s, 4H), 3.60 (s, 2H). LCMS (POS): 607.2 (M+H).

Workup

  1. washwashed with 10% LiCl (3×), brine (3×)
  2. dry with materialdried with sodium sulfate
  3. filtrationfiltered
  4. customThe crude product was purified by silica gel chromatography
  5. washeluting with 2% of MeOH in EtOAc
  6. additionThe fractions containing the desired product
  7. customwere further purified

Sources & evidence

ORD record
ord-5413bd3dcfb2465b988447e69452693d
Source dataset
uspto-grants-2015_11
Patent number
US09174947B2

Linked notes

Loading…