Sodium Carbonate → 4-(2-{[(3R)-1-Azabicyclo[2.2.2]oct-3-ylamino]carbonyl)-1-benzofuran-7-yl)-benzoic acid hydrochloride

HRID 1012770Notes

Reaction equation

HRID 1012770 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[O:14][C:15]3[C:21](Br)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[C:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)([OH:25])=[O:24].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[O:14][C:15]3[C:21]([C:29]4[CH:30]=[CH:31][C:26]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=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 3121834-Carboxyphenylboronic AcidHCID 67313982N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride

Product 1

HCID 673156904-(2-{[(3R)-1-Azabicyclo[2.2.2]oct-3-ylamino]carbonyl)-1-benzofuran-7-yl)-benzoic acid 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

150 mg (0.43 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 30A) and 71.3 mg (0.43 mmol) of 4-carboxyphenylboronic acid are introduced into 1.5 ml of DMF. Addition of 0.64 ml of 2 M sodium carbonate solution and 17.5 mg (0.02 mmol) of PdCl2(dppf) is followed by heating at 80° C. for 18 h. After cooling, the reaction mixture is filtered through kieselguhr, and the filtrate is concentrated and partitioned between water and ethyl acetate. The aqueous phase is washed with ethyl acetate and then concentrated. The crude product is purified by preparative HPLC. The product fractions are combined and concentrated and, after addition of a 3:1 mixture of acetonitrile and 1N hydrochloric acid, again concentrated. The crude product is stirred with acetonitrile. The precipitate is filtered off with suction and dried under high vacuum to result in 37 mg (20% of theory) of the title compound.

Workup

  1. temperatureAfter cooling
  2. filtrationthe reaction mixture is filtered through kieselguhr
  3. concentrationthe filtrate is concentrated
  4. custompartitioned between water and ethyl acetate
  5. washThe aqueous phase is washed with ethyl acetate
  6. concentrationconcentrated
  7. customThe crude product is purified by preparative HPLC
  8. concentrationconcentrated
  9. additionafter addition of a 3:1 mixture of acetonitrile and 1N hydrochloric acid
  10. concentrationagain concentrated
  11. filtrationThe precipitate is filtered off with suction
  12. customdried under high vacuum

Sources & evidence

ORD record
ord-137f1042c4e746258526cdf0c77ada3c
Source dataset
uspto-grants-2011_07
Patent number
US07977485B2

Reaction notes

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