Methyl iodide → Alosetron

HRID 2379157Notes

Reaction equation

HRID 2379157 reaction equation
[CH3:1][C:2]1[N:6](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:5]=[N:4][C:3]=1[CH2:26][N:27]1[CH2:39][CH2:38][C:30]2[NH:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:37]=3[C:29]=2[C:28]1=[O:40].[H-].[Na+].I[CH3:44]>CN(C=O)C.O.C1COCC1.C(O)(=O)C>[CH3:44][N:31]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:37]=2[C:29]2[C:28](=[O:40])[N:27]([CH2:26][C:3]3[N:4]=[CH:5][NH:6][C:2]=3[CH3:1])[CH2:39][CH2:38][C:30]1=2

Participants

8

Reactant 3

HCID 6328Methyl iodideHCID 24758Sodium hydrideHCID 15616330HCID 15616330, compound

Product 1

HCID 2099Alosetron

Reagents, catalysts & solvents 4

HCID 176Acetic AcidSolventHCID 962WaterSolvent2×HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

A solution of 2,3,4,5-tetrahydro-2[[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]methyl]-1H-pyrido[4,3-b]indol-1-one (261 mg) in dry DMF (25 ml) was treated with sodium hydride (60% dispersion in oil; 30 mg) and the mixture was stirred at room temperature under nitrogen for 15 min. Iodomethane (0.5M solution in DMF; 2 ml) was then added and stirring was continued for a further 15 min. The reaction mixture was then poured into water (100 ml) and the resulting suspension was extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with water (2×100 ml), dried and concentrated to give a solid. This was dissolved in a mixture of water (10 ml), THF (10 ml) and glacial acetic acid (10 ml) and heated at reflux for 2 h. After cooling, residual THF was removed in vacuo and the remaining solution was basified (to pH14) by addition of 2N sodium hydroxide. The resulting suspension was extracted with ethyl acetate (2×50 ml) and the combined, dried organic extracts were concentrated onto silica (Merck 7385). FCC eluting with System A (100:8:1) gave the title compound (81 mg) as a solid. The 1H-n.m.r. and t.l.c. data obtained for this material were consistent with those obtained for the product of Example 20.

Workup

  1. stirringstirring
  2. waitwas continued for a further 15 min
  3. extractionthe resulting suspension was extracted with ethyl acetate (2×50 ml)
  4. washThe combined organic extracts were washed with water (2×100 ml)
  5. customdried
  6. concentrationconcentrated
  7. customto give a solid
  8. temperatureheated
  9. temperatureat reflux for 2 h
  10. temperatureAfter cooling
  11. customresidual THF was removed in vacuo
  12. additionby addition of 2N sodium hydroxide
  13. extractionThe resulting suspension was extracted with ethyl acetate (2×50 ml)
  14. concentrationdried organic extracts were concentrated onto silica (Merck 7385)
  15. washFCC eluting with System A (100:8:1)

Sources & evidence

ORD record
ord-93270d64bb504df592e220fb8ec089e1
Source dataset
uspto-grants-1994_11
Patent number
US05360800

Reaction notes

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