Sodium Carbonate → N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-[3-(hydroxymethyl)phenyl]-1-benzofuran-2-carboxamide hydrochloride

HRID 1012773Notes

Reaction equation

HRID 1012773 reaction equation
[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21](Br)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[OH:23][CH2:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>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].CN(C=O)C>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([CH2:24][OH:23])[CH:30]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 2734662[3-(Hydroxymethyl)phenyl]boronic acidHCID 67313982N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride

Product 1

HCID 67314018N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-[3-(hydroxymethyl)phenyl]-1-benzofuran-2-carboxamide hydrochloride

Reagents, catalysts & solvents 2

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

Conditions

Temperature
60 °C

Procedure

150 mg (0.43 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 30A) and 65.3 mg (0.43 mmol) of 3-(hydroxymethyl)phenylboronic acid are introduced into 1.5 ml of DMF. Addition of 0.64 ml of 2 M sodium carbonate solution and 17.5 mg (0.02 mmol) of PdCl2(dppf) is followed by heating at 60° C. for 18 h. A further 17.5 mg (0.02 mmol) of PdCl2(dppf) are added and the mixture is stirred at 90° C. for a further 18 h. After cooling, the reaction mixture is filtered through kieselguhr. A first purification by preparative HPLC is followed by column chromatography on silica gel (mobile phase: dichloromethane/methanol/ammonia 90:9:1). The product fractions are combined and concentrated and, after addition of a 5:1 mixture of methanol and 4N hydrogen chloride in dioxane, again concentrated. Drying under high vacuum results in 45 mg (24% of theory) of the title compound.

Workup

  1. temperatureAfter cooling
  2. filtrationthe reaction mixture is filtered through kieselguhr
  3. customA first purification by preparative HPLC
  4. concentrationconcentrated
  5. additionafter addition of a 5:1 mixture of methanol and 4N hydrogen chloride in dioxane
  6. concentrationagain concentrated
  7. customDrying under high vacuum

Sources & evidence

ORD record
ord-11d9553a3be749aba717e15d00fba217
Source dataset
uspto-grants-2011_07
Patent number
US07977485B2

Reaction notes

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