Cesium carbonate → N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2,6-difluorophenyl)acetamide

HRID 576199Notes

Reaction equation

HRID 576199 reaction equation
CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][CH:12]=[N:13][CH:14]=2)O1.[CH2:16]([O:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:45])[CH2:35][C:36]2[C:41]([F:42])=[CH:40][C:39](Br)=[CH:38][C:37]=2[F:44])=[CH:29][C:28]=1[C:46]([F:49])([F:48])[F:47])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:50]([O-:53])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH2:16]([O:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:45])[CH2:35][C:36]2[C:41]([F:42])=[CH:40][C:39]([C:11]3[CH:12]=[N:13][C:14]([O:23][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:53][CH3:50])=[CH:19][CH:18]=4)=[C:9]([O:26][CH2:25][CH3:24])[CH:10]=3)=[CH:38][C:37]=2[F:44])=[CH:29][C:28]=1[C:46]([F:49])([F:48])[F:47])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 27346563-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineHCID 90416261N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2,6-difluorophenyl)acetamide

Product 1

HCID 90416829N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2,6-difluorophenyl)acetamideYield 70.3%

Reagents, catalysts & solvents 3

HCID 178418807HCID 178418807, compoundCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Procedure

A solution of 3-ethoxy-2-(4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (78 mg, 0.202 mmol), N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2,6-difluorophenyl)acetamide (110 mg, 0.202 mmol), PdCl2(dppf)-DCM adduct (16.50 mg, 0.020 mmol) and Cs2CO3 (132 mg, 0.404 mmol) in 1,4-dioxane (6 mL) and H2O (2 mL) was stirred at 110° C. for 15 min. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo. The residue was dissolved in DCM (60 mL) and washed with H2O (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC (DCM/MeOH=10/1) to yield N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2,6-difluorophenyl)acetamide (70 mg, 0.071 mmol, 35.1% yield): 1H NMR (400 MHz, CD3OD) δ 7.97 (d, J=2.0 Hz, 1H), 7.84 (s, 1H), 7.71 (d, J=11.2 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.39 (d, J=8.6 Hz, 2H), 7.37-7.13 (m, 8H), 6.90 (d, J=8.6 Hz, 2H), 5.39-5.34 (m, 2H), 4.61 (s, 2H), 4.27-4.20 (m, 2H), 4.18-4.10 (m, 2H), 3.86-3.82 (m, 2H), 3.78 (s, 3H), 1.42 (t, J=6.9 Hz, 3H), 1.19 (s, 2H); ES-LCMS m/z 723.2 (M+H).

Workup

  1. customthe solvent was removed in vacuo
  2. dissolutionThe residue was dissolved in DCM (60 mL)
  3. washwashed with H2O (20 mL) and brine (20 mL)
  4. dry with materialThe organic layer was dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude product was purified by preparative TLC (DCM/MeOH=10/1)

Sources & evidence

ORD record
ord-9681ffb449be4aa58dbc97f245d31d81
Source dataset
uspto-grants-2015_05
Patent number
US09035063B2

Reaction notes

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