Sodium Carbonate → 2-(1-Azabicyclo[2.2.2]oct-3-yl)-N-[4'-(hydroxymethyl)-1,1'-biphenyl-3-yl]acetamide Hydrochloride

HRID 722185Notes

Reaction equation

HRID 722185 reaction equation
[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[ClH:18].[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[CH:21]([CH2:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33](Br)[CH:32]=1)=[O:29])[CH2:20]2.[OH-].[Na+]>CN(C=O)C.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]>[ClH:18].[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[CH:21]([CH2:27][C:28]([NH:30][C:31]1[CH:32]=[C:33]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=3)[CH:34]=[CH:35][CH:36]=1)=[O:29])[CH2:20]2

Participants

7

Reactant 4

HCID 10340Sodium CarbonateHCID 14798Sodium HydroxideHCID 27347064-(Hydroxymethyl)benzeneboronic acid2×HCID 218834582-(1-Azabicyclo[2.2.2]oct-3-yl)-N-(3-bromophenyl)acetamide Hydrochloride

Product 1

HCID 218834612-(1-Azabicyclo[2.2.2]oct-3-yl)-N-[4'-(hydroxymethyl)-1,1'-biphenyl-3-yl]acetamide Hydrochloride

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)Catalyst2×HCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

24.0 mg (0.16 mmol) of 4-(hydroxymethyl)phenylboronic acid, 0.17 ml (0.34 mmol) of 2M aqueous sodium carbonate solution and 5.8 mg (0.01 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride are added to a solution of 75 mg (0.16 mmol) of 2-(1-azabicyclo[2.2.2]oct-3-yl)-N-(3-bromophenyl)acetamide hydrochloride in 1 ml of DMF. The reaction mixture is stirred at 80° C. for 14 h. A further 24.0 mg (0.16 mmol) of 4-(hydroxymethyl)phenylboronic acid, 23.2 mg (0.03 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride and 0.48 ml (0.48 mmol) of 1M sodium hydroxide solution are added. The mixture is then heated at 80° C. for a further 12 h. After the reaction is complete, the mixture is cooled, filtered through silica gel and then purified by preparative HPLC. The product fractions are concentrated, taken up in methanol, mixed with 4M HCl in dioxane and again concentrated. Drying under high vacuum results in 25.9 mg (39.8% of theory) of the title compound.

Workup

  1. temperatureThe mixture is then heated at 80° C. for a further 12 h
  2. temperaturethe mixture is cooled
  3. filtrationfiltered through silica gel
  4. custompurified by preparative HPLC
  5. concentrationThe product fractions are concentrated
  6. additionmixed with 4M HCl in dioxane
  7. concentrationagain concentrated
  8. customDrying under high vacuum

Sources & evidence

ORD record
ord-aabb0758d6d342f6bce84c4ff86b97f1
Source dataset
uspto-grants-2006_11
Patent number
US07138410B2

Reaction notes

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