Water → 3-amino-1'-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[3,2-f][1,2]benzisoxazole-5,3'-indol]-2'(1'H)-one

HRID 1407944Notes

Reaction equation

HRID 1407944 reaction equation
F[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]2[C:10]3([CH2:26][O:27][C:4]=2[CH:3]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:12]([CH2:19][C@H:20]1[CH2:24][CH2:23][CH2:22][O:21]1)[C:11]3=[O:25].CC(=[N:31][OH:32])C.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[NH2:9][C:8]1[C:7]2[CH:6]=[C:5]3[C:10]4([C:18]5[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=5)[N:12]([CH2:19][C@H:20]5[CH2:24][CH2:23][CH2:22][O:21]5)[C:11]4=[O:25])[CH2:26][O:27][C:4]3=[CH:3][C:2]=2[O:32][N:31]=1

Participants

6

Reactant 4

HCID 962WaterHCID 10796Cesium carbonateHCID 67180Acetone, oximeHCID 673577776-fluoro-2'-oxo-1'-[(2R)-tetrahydrofuran-2-ylmethyl]-1',2'-dihydrospiro[1-benzofuran-3,3'-indole]-5-carbonitrile

Product 1

HCID 673793143-amino-1'-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[3,2-f][1,2]benzisoxazole-5,3'-indol]-2'(1'H)-oneYield 60%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a stirred solution of 6-fluoro-2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile (0.59 g, 1.6 mol) and acetone oxime (0.35 g, 4.8 mmol) in N,N-dimethylformamide (20 mL) was added cesium carbonate (1.56 g, 4.8 mmol). The reaction mixture was stirred at ambient temperature for 19 h, then heated at 60° C. for 7 h and allowed to cool to ambient temperature. Water was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was dissolved in a mixture of ethanol (30 mL), water (10 mL), and concentrated hydrochloric acid (2 mL) and stirred at reflux for 4 h. The mixture was allowed to cool to ambient temperature and neutralized with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography and eluted with (ethyl acetate/hexanes (1/3)+0.1% v/v 7 N methanolic ammonia) to afford 3-amino-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one (0.37 g, 60%): mp 116-119° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.35-7.32 (m, 1H), 7.13-7.02 (m, 3H), 6.09 (s, 1H), 6.84-6.81 (m, 1H), 4.91 (ABq, 2H), 4.31-4.25 (m, 1H), 4.13-4.09 (m, 2H), 3.86-3.66 (m, 4H), 2.12-1.87 (m, 4H); (ES+) m/z 377.9 (M+1).

Workup

  1. temperatureheated at 60° C. for 7 h
  2. temperatureto cool to ambient temperature
  3. extractionthe mixture was extracted with ethyl acetate (3×50 mL)
  4. washThe combined organic extracts were washed with water and brine
  5. dry with materialdried over anhydrous sodium sulfate
  6. filtrationfiltered
  7. concentrationThe filtrate was concentrated in vacuo
  8. dissolutionThe residue was dissolved in a mixture of ethanol (30 mL), water (10 mL), and concentrated hydrochloric acid (2 mL)
  9. stirringstirred
  10. temperatureat reflux for 4 h
  11. temperatureto cool to ambient temperature and neutralized with saturated aqueous sodium bicarbonate
  12. extractionThe mixture was extracted with ethyl acetate (3×100 mL)
  13. washThe combined organic extracts were washed with water and brine
  14. dry with materialdried over anhydrous sodium sulfate
  15. filtrationfiltered
  16. concentrationThe filtrate was concentrated in vacuo
  17. washeluted with (ethyl acetate/hexanes (1/3)+0.1% v/v 7 N methanolic ammonia)

Sources & evidence

ORD record
ord-c36622c6b547483bb288d0ffdad44c6d
Source dataset
uspto-grants-2014_12
Patent number
US08916580B2

Reaction notes

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