Sodium Carbonate → 7-[3-(Acetylamino)phenyl]-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide hydrochloride

HRID 2179642Notes

Reaction equation

HRID 2179642 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.[C:29]([NH:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:31])[CH3:30].[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].[C:29]([NH:32][C:33]1[CH:38]=[C:37]([C:27]2[C:21]3[S:20][C:19]([C:17]([NH:16][C@H:10]4[CH:11]5[CH2:14][CH2:15][N:8]([CH2:13][CH2:12]5)[CH2:9]4)=[O:18])=[CH:23][C:22]=3[CH:24]=[CH:25][CH:26]=2)[CH:36]=[CH:35][CH:34]=1)(=[O:31])[CH3:30]

Participants

7

Reactant 4

HCID 10340Sodium CarbonateHCID 14798Sodium HydroxideHCID 157274(3-Acetamidophenyl)boronic acid2×HCID 67313990N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride

Product 1

HCID 674433167-[3-(Acetylamino)phenyl]-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-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

0.67 ml of 2 M sodium carbonate solution and 18.3 mg (0.02 mmol) of PdCl2(dppf) are added to a mixture of 200 mg (0.45 mmol) of N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 22A) and 80.2 mg (0.45 mmol) of 3-(acetamido)phenylboronic acid in 2 ml of DMF. The reaction mixture is heated at 80° C. for 17 h. A further 40.1 mg (0.22 mmol) of 3-(acetamido)phenylboronic acid, 1.34 ml of 1N sodium hydroxide solution and 73.2 mg (0.09 mmol) of PdCl2(dppf) are added, and the mixture is heated at 70° C. for a further 18 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 124.5 mg (59% of theory) of the title compound.

Workup

  1. temperaturethe mixture is heated at 70° C. for a further 18 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-80b9a48b399f42c5b5d341f83990a318
Source dataset
uspto-grants-2015_06
Patent number
US09067931B2

Reaction notes

Loading…