2,3-Dihydroxybutanedioic Acid → (2s,3r)-n-(2-((3-Pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide d-tartrate salt

HRID 45291Notes

Reaction equation

HRID 45291 reaction equation
[C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C@H:18]2[C@H:23]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=4[CH:31]=3)=[O:26])[CH:22]3[CH2:36][CH2:37][N:19]2[CH2:20][CH2:21]3)[CH:12]=1.C(OCC)(=O)C>C(O)C>[C:6]([C@H:4]([C@@H:2]([C:1]([OH:10])=[O:9])[OH:3])[OH:5])([OH:8])=[O:7].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C@H:18]2[C@H:23]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=4[CH:31]=3)=[O:26])[CH:22]3[CH2:36][CH2:37][N:19]2[CH2:20][CH2:21]3)[CH:12]=1

Participants

5

Reactant 3

HCID 8752,3-Dihydroxybutanedioic Acid2×HCID 8857Ethyl AcetateHCID 25147644Bradanicline

Product 1

HCID 66757387(2s,3r)-n-(2-((3-Pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide d-tartrate saltYield 159.3%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

Tartaric acid (25.6 mg, 0.173 mmol) was added to a solution of (2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide (125 mg, 0.346 mmol) in hot ethanol (1 mL). The resulting solution was slowly cooled to ambient temperature. No solids precipitated, so the solution was concentrated to give a white foam. Attempts to crystallize in isopropanol failed. The foam was dissolved in methanol and another half-equivalent of tartaric acid (25.6 mg, 0.173 mmol) was added. The mixture was concentrated to give a white foam, which would not crystallize from mixtures of methanol and isopropanol. The concentrated material (mixture of solid and gummy liquid) was then slurried in ethyl acetate (1 mL), producing a white solid. This was isolated by filtration (ethyl acetate wash) and drying in a vacuum oven (18 h at 40° C.), to give 141 mg (79.7% yield) of the mono stoichiometry salt (NMR), mp 136-140° C. Chiral LC analysis gave a purity of 98.1% (270 nm). 1H NMR (300 MHz, D2O) δ 8.50 (s, 1H), 8.01 (d, 1H), 7.86 (d, 1H), 7.75 (d, 1H), 7.56 (m, 2H), 7.38 (t, 1H), 7.32 (s, 1H), 7.21 (t, 1H), 4.34 (s, 2H, tartaric acid), 4.26 (d, 1H), 3.95 (m, 1H), 3.64 (m, 2H), 3.15-3.55 (m, 4H), 1.90-2.30 (m, 5H).

Workup

  1. customNo solids precipitated, so the solution
  2. concentrationwas concentrated
  3. customto give a white foam
  4. customto crystallize in isopropanol
  5. dissolutionThe foam was dissolved in methanol
  6. concentrationThe mixture was concentrated
  7. customto give a white foam, which would not
  8. customcrystallize from mixtures of methanol and isopropanol
  9. additionThe concentrated material (mixture of solid and gummy liquid)
  10. customproducing a white solid
  11. customdrying in a vacuum oven (18 h at 40° C.)

Sources & evidence

ORD record
ord-4ea280ae52b1423cb83ad19f9e86c7f4
Source dataset
uspto-grants-2013_09
Patent number
US08541446B2

Reaction notes

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