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

HRID 2179609Notes

Reaction equation

HRID 2179609 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.[N:29]1([C:35]2[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=2)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>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:38]4[CH:37]=[CH:36][C:35]([N:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)=[CH:40][CH:39]=4)=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 2795359(4-(Morpholin-4-yl)phenyl)boronic acidHCID 66904832N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride

Product 1

HCID 67313736N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-[4-(4-morpholinyl)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

0.22 ml of 2 M aqueous sodium carbonate solution and 6.1 mg (0.007 mmol) of PdCl2(dppf) are added to a mixture of 60 mg (0.15 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 30.9 mg (0.15 mmol) of 4-(4-morpholinyl)phenylboronic acid in 1 ml of DMF. The reaction mixture is heated to 80° C. After 4.5 h, a further 6.1 mg (0.007 mmol) of PdCl2(dppf) are added. After a further 12 h, the reaction mixture is filtered through kieselguhr and evaporated to dryness. The crude product is purified by preparative HPLC. The product is dissolved in methanol, and an excess of 4N hydrogen chloride in dioxane is added. Drying under high vacuum results in 20.6 mg (25% of theory) of the title compound.

Workup

  1. waitAfter a further 12 h
  2. filtrationthe reaction mixture is filtered through kieselguhr
  3. customevaporated to dryness
  4. customThe crude product is purified by preparative HPLC
  5. dissolutionThe product is dissolved in methanol
  6. additionan excess of 4N hydrogen chloride in dioxane is added
  7. customDrying under high vacuum

Sources & evidence

ORD record
ord-8dd481f636b44b8eb11d802813817485
Source dataset
uspto-grants-2015_06
Patent number
US09067931B2

Reaction notes

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