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

HRID 576232Notes

Reaction equation

HRID 576232 reaction equation
[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][CH3:17])[C:12](I)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([O:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:55])[CH2:38][C:39]2[CH:44]=[CH:43][C:42](B3OC(C)(C)C(C)(C)O3)=[CH:41][C:40]=2[F:54])=[CH:32][C:31]=1[C:56]([F:59])([F:58])[F:57])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([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]>[CH2:1]([O:8][C:9]1[N:10]=[CH:11][C:12]([C:42]2[CH:43]=[CH:44][C:39]([CH2:38][C:37]([NH:36][C:33]3[CH:34]=[CH:35][C:30]([O:29][CH2:28][CH2:27][O:26][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[C:31]([C:56]([F:57])([F:59])[F:58])[CH:32]=3)=[O:55])=[C:40]([F:54])[CH:41]=2)=[C:13]([O:15][CH2:16][CH3:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 90416295N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamideHCID 904176602-(Benzyloxy)-4-ethoxy-5-iodopyridine

Product 1

HCID 904184152-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-2-fluorophenyl)-N-(4-(2-(benzyloxy) ethoxy)-3-(trifluoromethyl)phenyl)acetamideYield 24.1%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A suspension of 2-(benzyloxy)-4-ethoxy-5-iodopyridine (80 mg, 0.225 mmol), N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (129 mg, 0.225 mmol), PdCl2(dppf) (16.48 mg, 0.023 mmol), Cs2CO3 (73.4 mg, 0.225 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was heated to 100° C. for 20 min under a N2 atmosphere in a microwave. Then the mixture was concentrated to give the residue which was extracted with DCM (20 mL×2). The organic extract was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC (EA/PE=1:1, Rf=0.5) to yield 2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-2-fluorophenyl)-N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)acetamide (60 mg, 0.054 mmol, 24.1% yield): 1H NMR (400 MHz, CD3OD) δ 7.95 (s., 1H), 7.85-7.84 (d, J=2.4 Hz, 1H), 7.74-7.71 (dd, J=8.8, 2.4 Hz, 1H), 7.44-7.42 (m, 2H), 7.38-7.24 (m, 10H), 7.16-7.14 (d, J=8.8 Hz, 1H), 6.48 (s, 1H), 5.35 (s, 2H), 4.61 (s, 2H), 4.23 (t, J=4.6 Hz, 2H), 4.15-4.10 (m, 3H), 3.84 (t, J=4.6 Hz, 2H), 3.77 (s, 2H), 3.66-3.65 (m, 1H), 3.55-3.54 (m, 1H), 1.36 (t, J=7.2 Hz, 3H); ES-LCMS m/z 721 (M+H).

Workup

  1. concentrationThen the mixture was concentrated
  2. customto give the residue which
  3. extractionwas extracted with DCM (20 mL×2)
  4. extractionThe organic extract
  5. washwas washed with brine
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe crude product was purified by preparative TLC (EA/PE=1:1, Rf=0.5)

Sources & evidence

ORD record
ord-8b5979a85efb4171bc78b9c95ad907e2
Source dataset
uspto-grants-2015_05
Patent number
US09035063B2

Reaction notes

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