Trifluoromethanesulfonic anhydride → HCID 67342411, compound

HRID 1669472Notes

Reaction equation

HRID 1669472 reaction equation
[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:33]([O:35][CH3:36])=[O:34])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][C:16]2([CH2:30]OC(C)(C)O[CH2:26]2)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[NH2:61][CH2:62][CH2:63][N:64]1[CH2:69][CH2:68][N:67](C(OC(C)(C)C)=O)[CH2:66][CH2:65]1.[S:77](N)([NH2:80])(=[O:79])=[O:78]>CO.C1COCC1>[NH2:80][S:77]([N:67]1[CH2:68][CH2:69][N:64]([CH2:63][CH2:62][N:61]2[CH2:30][C:16]3([CH2:15][N:14]4[C:13]5[CH:12]=[C:11]([C:33]([O:35][CH3:36])=[O:34])[CH:10]=[CH:9][C:8]=5[C:7]([CH:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)=[C:21]4[C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[O:18][CH2:17]3)[CH2:26]2)[CH2:65][CH2:66]1)(=[O:79])=[O:78]

Participants

7

Reactant 5

HCID 67749Trifluoromethanesulfonic anhydrideHCID 81531Diisopropylethylamine2×HCID 82267SulfamideHCID 1514400tert-Butyl 4-(2-aminoethyl)piperazine-1-carboxylateHCID 50994682HCID 50994682, compound

Product 1

HCID 67342411HCID 67342411, compoundYield 40%

Reagents, catalysts & solvents 1

HCID 21899815MeOH tetrahydrofuranSolvent

Procedure

Cat. TsOH monohydrate was added to a suspension of methyl 14′-cyclohexyl-2,2-dimethylspiro[1,3-dioxane-5,7′-indolo[1,2-e][1,5]benzoxazocine]-11′-carboxylate in MeOH/THF 1:2 (0.03 M), and the solution was stirred at RT for 3 h. Filtration on a pad of neutral alumina using EtOAc as eluent afforded after evaporation of the solvent in vacuo methyl 14-cyclohexyl-7,7-bis(hydroxymethyl)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (quant). This material was dissolved in dry MeCN (0.2M) and DIPEA (4.0 eq) and trifluoromethane sulfonic anhydride (3.5 eq) was added at 0° C. The mixture was stirred at 0° C. for 15 min, then more DIPEA (4 eq) was added at RT. Tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (2 eq) was added, and the mixture was stirred at 70° C. for 1 h. After removal of the solvent in vacuo EtOAc was added, the solution was washed with H2O and brine, dried over Na2SO4 and the solvent was removed in vacuo. The crude methyl 1-{2-[4-(tert-butoxycarbonyl)piperazin-1-yl]ethyl}-14′-cyclohexylspiro[azetidine-3,7′-indolo[1,2-e][1,5]benzoxazocine]-11′-carboxylate was taken in DCM/TFA 3:1 (0.13M) and stirred at RT for 2 h. The mixture was evaporated to dryness and the residual material was dissolved in EtOAc. The solution was washed with sat. aq. NaHCO3 and brine. The organic phase was dried over Na2SO4 and the solvent evaporated in vacuo. The residue was dissolved in dry dioxane (0.06M) and sulfamide (5 eq) was added. The mixture was stirred at reflux for 3 h, then overnight at RT. The residue obtained after evaporation was purified by FC (EtOAc/MeOH, 9:1) to afford the title compound in 40% yield. (ES+) m/z 622 (M+H)+.

Workup

  1. filtrationFiltration on a pad of neutral alumina
  2. customafforded
  3. customafter evaporation of the solvent in vacuo methyl 14-cyclohexyl-7,7-bis(hydroxymethyl)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (quant)
  4. dissolutionThis material was dissolved in dry MeCN (0.2M)
  5. stirringThe mixture was stirred at 0° C. for 15 min
  6. stirringthe mixture was stirred at 70° C. for 1 h
  7. customAfter removal of the solvent in vacuo EtOAc
  8. additionwas added
  9. washthe solution was washed with H2O and brine
  10. dry with materialdried over Na2SO4
  11. customthe solvent was removed in vacuo
  12. stirringstirred at RT for 2 h
  13. customThe mixture was evaporated to dryness
  14. dissolutionthe residual material was dissolved in EtOAc
  15. washThe solution was washed with sat. aq. NaHCO3 and brine
  16. dry with materialThe organic phase was dried over Na2SO4
  17. customthe solvent evaporated in vacuo
  18. dissolutionThe residue was dissolved in dry dioxane (0.06M)
  19. stirringThe mixture was stirred
  20. temperatureat reflux for 3 h
  21. customovernight
  22. customat RT
  23. customThe residue obtained
  24. customafter evaporation
  25. customwas purified by FC (EtOAc/MeOH, 9:1)

Sources & evidence

ORD record
ord-aad6e3ba715f43968764819be29f1cc6
Source dataset
uspto-grants-2011_08
Patent number
US07989438B2

Reaction notes

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