Ethanol → (R)-N-{4-[6-(1-Aza-bicyclo[2.2.2]oct-3-yloxy)-pyridazin-3-yl]-phenyl}-acetamide

HRID 1441432Notes

Reaction equation

HRID 1441432 reaction equation
Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C@@H:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=2)O1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.O1CCOCC1>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12]1)[C@@H:9]([O:8][C:5]1[N:6]=[N:7][C:2]([C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=3)=[CH:3][CH:4]=1)[CH2:10]2

Participants

8

Reactant 4

HCID 702EthanolHCID 10340Sodium CarbonateHCID 27346194'-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)acetanilideHCID 86598842(3R)-3-[(6-chloropyridazin-3-yl)oxy]quinuclidine

Product 1

HCID 11151914(R)-N-{4-[6-(1-Aza-bicyclo[2.2.2]oct-3-yloxy)-pyridazin-3-yl]-phenyl}-acetamideYield 79%

Reagents, catalysts & solvents 3

HCID 27342162-(Dicyclohexylphosphino)biphenylCatalystHCID 178418476HCID 178418476, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
150 °C

Procedure

The product of Example 9A (182 mg, 0.76 mmol), N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetamide (Aldrich, 500 mg, 1.9 mmol), dichlorobis(triphenylphosphine)palladium (II) (Aldrich, 53 mg, 0.076 mmol) and 2-(dicyclohexylphosphino)biphenyl (Strem Chemicals, 6.5 mg, 0.019 mmol) were combined with 1 mL each of ethanol, p-dioxane, and 1 M aq. sodium carbonate. The mixture was heated in a sealed tube to 150° C. at 330 watts for 10 min in an Emry™ Creator microwave. The mixture was cooled to room temperature, filtered through Celite®, and concentrated onto silica. The product was purified by column chromatography (SiO2, 5% methanol containing 1% NH4OH—CH2Cl2) to provide the title compound (203 mg, 79%). 1H NMR (300 MHz, CD3OD) δ 1.96 (m, 1H), 2.09 (m, 1H), 2.16 (m, 1H), 2.16 (s, 3H), 2.38 (m, 1H), 2.64 (td, J=6.5, 3.6 Hz, 1H), 3.33-3.53 (m, 6H), 3.97 (dd, J=13.9, 8.1 Hz, 1H), 5.54 (m, 1H), 7.32 (d, J=9.4 Hz, 1H), 7.69-7.78 (m, 2H), 7.91-7.98 (m, 2H), 8.11 (d, J=9.3 Hz, 1H) ppm; MS (DCI/NH3): m/z 339 (M+H)+.

Workup

  1. temperatureThe mixture was cooled to room temperature
  2. filtrationfiltered through Celite®
  3. concentrationconcentrated onto silica
  4. customThe product was purified by column chromatography (SiO2, 5% methanol containing 1% NH4OH—CH2Cl2)

Sources & evidence

ORD record
ord-621bf8ad7b0f4af9a9b6198674d50df5
Source dataset
uspto-grants-2010_02
Patent number
US07655657B2

Reaction notes

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