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

HRID 1012737Notes

Reaction equation

HRID 1012737 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 66904832N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride

Product 1

HCID 673140087-[3-(Acetylamino)phenyl]-N-[(3R)-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

0.75 ml of 2 M aqueous sodium carbonate solution and 20.3 mg (0.02 mmol) of PdCl2(dppf) are added to a mixture of 200 mg (0.50 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 89.1 mg (0.50 mmol) of 3-(acetamido)phenylboronic acid in 2 ml of DMF. The reaction mixture is heated at 80° C. for 17 h. A further 89.1 mg (0.50 mmol) of 3-(acetamido)phenylboronic acid, 1.5 ml of 1N sodium hydroxide solution and 81.3 mg (0.1 mmol) of PdCl2(dppf) are added, and the mixture is heated at 86° C. for a further 18 h. After cooling, it is filtered through kieselguhr and purified by preparative HPLC. The resulting crude product is further purified by flash chromatography on silica gel (mobile phase: dichloromethane/methanol/ammonia 100:10:2). 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 243.2 mg (86.6% of theory) of the title compound.

Workup

  1. temperaturethe mixture is heated at 86° C. for a further 18 h
  2. temperatureAfter cooling
  3. filtrationit is filtered through kieselguhr
  4. custompurified by preparative HPLC
  5. customThe resulting crude product is further purified by flash chromatography on silica gel (mobile phase: dichloromethane/methanol/ammonia 100:10:2)
  6. concentrationThe product fractions are concentrated
  7. concentration1-mixture of methanol and 1N hydrochloric acid and again concentrated
  8. customDrying under high vacuum

Sources & evidence

ORD record
ord-7ebee4c03fe44a598c20779daa36c537
Source dataset
uspto-grants-2011_07
Patent number
US07977485B2

Reaction notes

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