Cesium carbonate → 2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-3-fluorophenyl)-N-(4-cyano-3-(trifluoromethyl)phenyl)acetamide

HRID 1050053Notes

Reaction equation

HRID 1050053 reaction equation
[CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH2:24])=[O:23])=[CH:17][C:16]=2[F:25])=[C:11]([O:26][CH2:27][CH3:28])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[C:32]([C:38]([F:41])([F:40])[F:39])[CH:31]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:24][C:30]3[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[C:32]([C:38]([F:39])([F:40])[F:41])[CH:31]=3)=[O:23])=[CH:17][C:16]=2[F:25])=[C:11]([O:26][CH2:27][CH3:28])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 223378254-Bromo-2-(trifluoromethyl)benzonitrileHCID 904164292-(4-(6-(Benzyloxy)-4-ethoxypyridin-3-yl)-3-fluorophenyl)acetamide

Product 1

HCID 904159812-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-3-fluorophenyl)-N-(4-cyano-3-(trifluoromethyl)phenyl)acetamideYield 28.5%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Procedure

A solution of 2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-3-fluorophenyl)acetamide (20 mg, 0.053 mmol), 4-bromo-2-(trifluoromethyl)benzonitrile (13.14 mg, 0.053 mmol), Pd2(dba)3 (4.81 mg, 5.26 μmol), Xantphos (3.04 mg, 5.26 μmol) and Cs2CO3 (34.3 mg, 0.105 mmol) in 1,4-dioxane (2 mL) was stirred at 120° C. for 1 h. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo. The residue was dissolved in EA (20 mL) and washed with H2O (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by preparative TLC (PE/EA=2/1) to yield 2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-3-fluorophenyl)-N-(4-cyano-3-(trifluoromethyl)phenyl)acetamide (12 mg, 0.015 mmol, 28.5% yield): 1H NMR (400 MHz, CD3OD) δ 8.25 (s, 1H), 8.01 (d, J=8.6 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.84 (s, 1H), 7.59-7.48 (m, 1H), 7.43-7.28 (m, 5H), 7.23-7.15 (m, 2H), 6.46 (s, 1H), 5.34 (s, 2H), 4.09 (m, 2H), 3.73 (s, 3H), 1.28 (t, J=6.4 Hz, 3H); ES-LCMS m/z 550.1 (M+H).

Workup

  1. customthe solvent was removed in vacuo
  2. dissolutionThe residue was dissolved in EA (20 mL)
  3. washwashed with H2O (10 mL) and brine (10 mL)
  4. dry with materialThe organic layer was dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude material was purified by preparative TLC (PE/EA=2/1)

Sources & evidence

ORD record
ord-47565675b9e0446499727880db5bbd34
Source dataset
uspto-grants-2016_07
Patent number
US09382238B2

Reaction notes

Loading…