Sodium Carbonate → N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-[4-(dimethylamino)phenyl]-1-benzothiophene-2-carboxamide hydrochloride

HRID 2179618Notes

Reaction equation

HRID 2179618 reaction equation
C(=O)([O-])[O-].[Na+].[Na+].[ClH:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([NH:16][C:17]([C:19]1[S:20][C:21]3[C:27](Br)=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2.[CH3:29][N:30]([CH3:40])[C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.[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:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([NH:16][C:17]([C:19]1[S:20][C:21]3[C:27]([C:34]4[CH:35]=[CH:36][C:31]([N:30]([CH3:40])[CH3:29])=[CH:32][CH:33]=4)=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2

Participants

7

Reactant 4

HCID 10340Sodium CarbonateHCID 14798Sodium HydroxideHCID 27343444-(Dimethylamino)phenylboronic acid2×HCID 66904832N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride

Product 1

HCID 67313516N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-[4-(dimethylamino)phenyl]-1-benzothiophene-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
80 °C

Procedure

0.33 ml of 2 M sodium carbonate solution and 9.1 mg (0.01 mmol) of PdCl2(dppf) are added to a mixture of 100 mg (0.22 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 36.8 mg (0.22 mmol) of 4-(dimethylamino)phenylboronic acid in 1 ml of DMF. The reaction mixture is heated at 80° C. for 16 h. A further 36.8 mg (0.22 mmol) of 4-(dimethylamino)phenylboronic acid, 36.5 mg (0.04 mmol) of PdCl2(dppf) and 0.67 ml of 1N sodium hydroxide solution are added, and the mixture is heated at 80° C. for a further 3 h. Cooling is followed by filtration through kieselguhr and purification by preparative HPLC. The product fractions are concentrated, taken up in a 5:1 mixture of methanol and 1N hydrochloric acid and again concentrated. Drying under high vacuum results in 50.6 mg-(47% of theory) of the title compound.

Workup

  1. temperaturethe mixture is heated at 80° C. for a further 3 h
  2. temperatureCooling
  3. filtrationis followed by filtration through kieselguhr and purification by preparative HPLC
  4. concentrationThe product fractions are concentrated
  5. additiontaken up in a 5:1 mixture of methanol and 1N hydrochloric acid
  6. concentrationagain concentrated
  7. customDrying under high vacuum

Sources & evidence

ORD record
ord-c4448bfbcd7c4bad84a541c0065a5c23
Source dataset
uspto-grants-2015_06
Patent number
US09067931B2

Reaction notes

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