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

HRID 2179610Notes

Reaction equation

HRID 2179610 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[C:21](Br)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[OH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>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].CN(C=O)C>[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:21]([C:28]4[CH:29]=[CH:30][C:25]([CH2:24][OH:23])=[CH:26][CH:27]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 27347064-(Hydroxymethyl)benzeneboronic acidHCID 66904832N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride

Product 1

HCID 67313350N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-[4-(hydroxymethyl)phenyl]-1-benzothiophene-2-carboxamide hydrochloride

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

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 22.7 mg (0.15 mmol) of 4-(hydroxymethyl)phenylboronic acid are introduced into 1 ml of DMF. Addition of 0.22 ml of 2 M aqueous sodium carbonate solution and 6.1 mg (0.01 mmol) of PdCl2(dppf) is followed by heating to 80° C. After 14 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 9 mg (9% of theory) of the title compound.

Workup

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

Sources & evidence

ORD record
ord-57109484bb0d4d4f84710ac6548fc349
Source dataset
uspto-grants-2015_06
Patent number
US09067931B2

Reaction notes

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