HOAt → N-(3-Fluoro-4-(7-methoxyquinolin-4-yloxy)phenyl)-3-oxo-4-phenylmorpholine-2-carboxamide

HRID 415931Notes

Reaction equation

HRID 415931 reaction equation
[O:1]=[C:2]1[CH:7]([C:8]([O-:10])=O)[O:6][CH2:5][CH2:4][N:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Li+].Cl.C([NH+](CC)CC)C.N1C2C(=NC=CC=2)N(O)N=1.[F:36][C:37]1[CH:38]=[C:39]([NH2:56])[CH:40]=[CH:41][C:42]=1[O:43][C:44]1[C:53]2[C:48](=[CH:49][C:50]([O:54][CH3:55])=[CH:51][CH:52]=2)[N:47]=[CH:46][CH:45]=1>>[F:36][C:37]1[CH:38]=[C:39]([NH:56][C:8]([CH:7]2[O:6][CH2:5][CH2:4][N:3]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:2]2=[O:1])=[O:10])[CH:40]=[CH:41][C:42]=1[O:43][C:44]1[C:53]2[C:48](=[CH:49][C:50]([O:54][CH3:55])=[CH:51][CH:52]=2)[N:47]=[CH:46][CH:45]=1

Participants

5

Reactant 4

HCID 181649HOAtHCID 21900368Triethylammonium hydrochlorideHCID 59598343Lithium 3-oxo-4-phenylmorpholine-2-carboxylateHCID 595983543-Fluoro-4-(7-methoxyquinolin-4-yloxy)benzenamine

Product 1

HCID 45274413N-(3-Fluoro-4-(7-methoxyquinolin-4-yloxy)phenyl)-3-oxo-4-phenylmorpholine-2-carboxamideYield 15.2%

Procedure

A dry, 10 mL schlenk-type flask was charged with a stirbar, lithium 3-oxo-4-phenylmorpholine-2-carboxylate (0.096 g, 0.42 mmol), triethylammonium hydrochloride (0.058 g, 0.42 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (0.072 g, 0.53 mmol), and evacuated. The flask was back-filled with nitrogen and treated with 2 mL dry THF and 1 mL dry NMP. To the stirring solution was added Si-DCC (0.55 g, 0.53 mmol) followed by 3-fluoro-4-(7-methoxyquinolin-4-yloxy)benzenamine (0.100 g, 0.35 mmol). The reaction was stirred for 3 d at RT, and then 60° C. for 24 h. The slurry was filtered through a 0.22 μm frit, and the THF removed. The crude was purified by HPLC (Waters Spherisorb S5 column (PN PSS830195, 20×250 mm, 60 Å pore, 5 μm particle size)) to afford the title compound (0.026 g, 15.2% yield) 1H NMR (400 MHz, Chloroform-d) 3.74 (ddd, J=12.32, 3.72, 3.52 Hz, 1 H), 3.95-4.03 (m, 4 H), 4.23 (dt, J=12.42, 3.91 Hz, 1 H), 4.27-4.38 (m, 1 H), 5.06 (s, 1 H), 6.37 (dd, J=5.23, 1.12 Hz, 1 H), 7.20 (t, J=8.56 Hz, 1 H), 7.24 (dd, J=9.15, 2.49 Hz, 1 H), 7.27 (ddd, J=8.83, 2.47, 1.12 Hz, 1 H), 7.32-7.41 (m, 3 H), 7.43 (d, J=2.45 Hz, 1 H), 7.46-7.51 (m, 2 H), 7.81 (dd, J=12.03, 2.35 Hz, 1 H), 8.26 (d, J=9.19 Hz, 1 H), 8.59 (d, J=5.18 Hz, 1 H), 9.66 (br. s., 1 H). MS (ESI pos. ion) m/z=488, calc'd for C27H22FN3O5 487.

Workup

  1. customevacuated
  2. additionThe flask was back-filled with nitrogen
  3. additiontreated with 2 mL dry THF and 1 mL dry NMP
  4. wait60° C. for 24 h
  5. filtrationThe slurry was filtered through a 0.22 μm frit
  6. customthe THF removed
  7. customThe crude was purified by HPLC (Waters Spherisorb S5 column (PN PSS830195, 20×250 mm, 60 Å pore, 5 μm particle size))

Sources & evidence

ORD record
ord-b3ba25e52216469bae1dfe715b93363b
Source dataset
uspto-grants-2012_01
Patent number
US08088794B2

Reaction notes

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