Cesium carbonate → N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl) acetamide

HRID 576235Notes

Reaction equation

HRID 576235 reaction equation
BrC1C=CC([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[CH2:21][CH2:20]3)=[C:14]([C:27]([F:30])([F:29])[F:28])[CH:13]=2)=[O:10])=C(F)C=1.CC1(C)C(C)(C)OB(C2C=CC=NC=2)O1.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]>[CH2:25]([N:22]1[CH2:23][CH2:24][N:19]([CH2:18][C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:9](=[O:10])[CH3:8])=[CH:13][C:14]=2[C:27]([F:29])([F:28])[F:30])[CH2:20][CH2:21]1)[CH3:26]

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 27346563-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineHCID 904158182-(4-bromo-2-fluorophenyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamide

Product 1

HCID 71262054N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl) acetamideYield 72.4%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolvent2×HCID 312751,4-DioxaneSolvent2×

Procedure

A suspension of 2-(4-bromo-2-fluorophenyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamide (413 mg, 0.822 mmol) in 1,4-dioxane (3 mL) and H2O (1 mL) was added to a solution of 3-ethoxy-2-(4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (317 mg, 0.822 mmol) in 1,4-dioxane (3 mL) and H2O (1 mL). PdCl2(dppf) (60.2 mg, 0.082 mmol) and Cs2CO3 (536 mg, 1.644 mmol) were added and the mixture was at 110° C. for 30 min in a microwave. The mixture was cooled to rt. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by preparative TLC (PE/EA=1/1, Rf=0.5) to yield a light yellow solid of 2-(4-(5-ethoxy-6-(4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl) acetamide (405 mg, 0.595 mmol, 72.4% yield): 1H NMR (400 MHz, CD3OD) δ 8.02-7.87 (m, 2H), 7.82-7.64 (m, 2H), 7.60-7.30 (m, 6H), 6.98-6.80 (m, 2H), 5.34 (s, 2H), 4.18-4.04 (m, 2H), 3.84-3.72 (m, 4H), 3.68-3.57 (m, 2H), 2.91-2.38 (m, 10H), 1.47-1.31 (m, 3H), 1.14 (s, 3H); ES-LCMS m/z 681.3 (M+H).

Workup

  1. concentrationThen the solution was concentrated
  2. extractionThe combined organic extract
  3. washwas washed with brine
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude material was purified by preparative TLC (PE/EA=1/1, Rf=0.5)

Sources & evidence

ORD record
ord-9261796e8f334586b4ab1e81d480332a
Source dataset
uspto-grants-2015_05
Patent number
US09035063B2

Reaction notes

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