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Cesium carbonate → N-(3,4-dichlorophenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide

HRID 576228
Notes
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Reaction equation

HRID 576228 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)=[O:10])=[C:4]([F:20])[CH:3]=1.[CH2:21]([O:23][C:24]1[C:25]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)=[N:26][CH:27]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:29]=1)[CH3:22].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C(Cl)Cl.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]>[Cl:19][C:14]1[CH:13]=[C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:28]3[CH:27]=[N:26][C:25]([O:39][CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=4)=[C:24]([O:23][CH2:21][CH3:22])[CH:29]=3)=[CH:3][C:4]=2[F:20])[CH:17]=[CH:16][C:15]=1[Cl:18]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 3

HCID 10796Cesium carbonateHCID 904167753-Ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineHCID 904170062-(4-bromo-2-fluorophenyl)-N-(3,4-dichlorophenyl)acetamide

Product 1

HCID 90415929N-(3,4-dichlorophenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamideYield 52.8%

Reagents, catalysts & solvents 4

HCID 44119782Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)Catalyst
HCID 962WaterSolvent
HCID 6344DichloromethaneSolvent
HCID 312751,4-DioxaneSolvent

Conditions

Temperature
130 °C

Procedure

To a solution of 2-(4-bromo-2-fluorophenyl)-N-(3,4-dichlorophenyl)acetamide (60 mg, 0.159 mmol), 3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (61.3 mg, 0.159 mmol) and Cs2CO3 (156 mg, 0.477 mmol) in 1,4-dioxane (3 mL) and H2O (1 mL) was added PdCl2(dppf) (11.64 mg, 0.016 mmol) in one charge. The mixture was stirred at 130° C. in the microwave for 30 min. After LCMS analysis showed the starting material had disappeared, the mixture was filtered. The filtrate was concentrated and evaporated to dryness to give crude product which was dissolved in DCM and washed with H2O and brine. Then the crude product was purified by preparative TLC (DCM/MeOH=40/1) to give pure product N-(3,4-dichlorophenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (60.0 mg, 0.084 mmol, 52.7% yield): 1H NMR: (400 MHz, CD3OD) δ 7.95 (d, J=2.0 Hz, 1H), 7.92 (d, J=1.8 Hz, 1H), 7.45 (s, 3H), 7.43-7.37 (m, 5H), 6.91 (d, J=8.6 Hz, 2H), 5.37 (s, 2H), 4.15 (m, 3H), 3.79 (s, 4H), 1.42 (t, J=7.0 Hz, 3H); ES-LCMS: m/z 435 (M-120).

Workup

  1. additioncharge
  2. filtrationthe mixture was filtered
  3. concentrationThe filtrate was concentrated
  4. customevaporated to dryness
  5. customto give crude product which
  6. washwashed with H2O and brine
  7. customThen the crude product was purified by preparative TLC (DCM/MeOH=40/1)

Sources & evidence

ORD record
ord-d6d60a4278e84b7aa16075fb901f8030
Source dataset
uspto-grants-2015_05
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09035063B2

Reaction notes

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