Benzophenone imine → 7-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride

HRID 15475

Reaction equation

HRID 15475 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[S:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]=1Br)=[O:12])[CH2:3]2.C(=[NH:36])(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[ClH:1].[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[S:14][C:15]3[C:22]([NH2:36])=[CH:21][CH:20]=[CH:19][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2

Participants

6

Reactant 4

HCID 136809Benzophenone imineHCID 634876Binap, (A+-)-HCID 23676156Sodium t-butoxideHCID 66904553N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-bromo-1-benzothiophene-2-carboxamide hydrochloride

Product 1

HCID 669037637-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride

Reagents, catalysts & solvents 1

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×

Conditions

Temperature
80 °C

Procedure

87 mg (0.22 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-bromo-1-benzo-thiopene-2-carboxamide hydrochloride, 47.1 mg (0.26 mmol) of benzophenone-imine, 12.1 mg (0.02 mmol) of rac-BINAP, 45.8 mg (0.48 mmol) of sodium tert-butoxide and 6.0 mg (0.01 mmol) of Pd2(dba)3 are, under argon, added to a flask which has been dried by heating. 1.5 ml of toluene are added, and the reaction mixture is heated at 80° C. After 30 min, 0.5 ml of THF is added, followed by a further 6.0 mg (0.01 mmol) of Pd2(dba)3 after 6 h. After a further 6 h, the mixture is filtered (0.45 μm filter) and then purified by preparative HPLC. The resulting benzophenoneimine adduct is dissolved in a 1:1 mixture of THF and methanol with addition of 20% by volume of 1N hydrochloric acid. After 1 h at RT, the reaction mixture is concentrated. The solid formed is triturated with acetonitrile and filtered off. Drying under high vacuum gives 17 mg (21% of theory) of the title compound.

Workup

  1. additionadded to a flask which
  2. customhas been dried
  3. temperatureby heating
  4. addition1.5 ml of toluene are added
  5. addition0.5 ml of THF is added
  6. waitAfter a further 6 h
  7. filtrationthe mixture is filtered
  8. filtration(0.45 μm filter)
  9. custompurified by preparative HPLC
  10. dissolutionThe resulting benzophenoneimine adduct is dissolved in a 1:1 mixture of THF and methanol with addition of 20% by volume of 1N hydrochloric acid
  11. waitAfter 1 h at RT
  12. concentrationthe reaction mixture is concentrated
  13. customThe solid formed
  14. customis triturated with acetonitrile
  15. filtrationfiltered off
  16. customDrying under high vacuum

Sources & evidence

ORD record
ord-87ceca1cba724d6e948f841a569bc855
Source dataset
uspto-grants-2010_06
Patent number
US07732477B2

Linked notes

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