N,N-Diethylethylenediamine → HCID 59142810, compound

HRID 1518239Notes

Reaction equation

HRID 1518239 reaction equation
[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:33]([O:35]C)=[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.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.CCN(C(C)C)C(C)C.[CH2:61]([N:63]([CH2:67][CH3:68])[CH2:64][CH2:65][NH2:66])[CH3:62]>CO.C1COCC1.CC#N>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:33]([OH:35])=[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][N:66]([CH2:65][CH2:64][N:63]([CH2:67][CH3:68])[CH2:61][CH3:62])[CH2:26]2)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

7

Reactant 4

HCID 60993N,N-DiethylethylenediamineHCID 67749Trifluoromethanesulfonic anhydrideHCID 81531Diisopropylethylamine2×HCID 50994682HCID 50994682, compound

Product 1

HCID 59142810HCID 59142810, compoundYield 25%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 21899815MeOH tetrahydrofuranSolvent

Procedure

TsOH monohydrate (1 eq.) 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 (Example 2, Step 3) in MeOH/THF 1:3 (0.03 M), and the solution was stirred at RT for 6 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 (91%). Triflic anhydride (3.5 eq) was added at 0° C. to a solution of this material in dry MeCN (0.05M), DIPEA (4.0 eq) was added and the mixture was stirred at 0° C. for 15 min, then further 4.0 eq of DIPEA were added; N,N-diethylethane-1,2-diamine (2 eq) was added, and the mixture was stirred at 70° C. for 2 h. After removal of the solvent EtOAc was added, the organic phase was washed with water and brine, dried over Na2SO4 and the solvent was removed in vacuo. The residue was hydrolysed with aq. 1N KOH in dioxane (75° C., 2 h) under degassed conditions; after quenching at 0° C. with 1N HCl evaporation to dryness gave a residue that was purified by RP-HPLC to afford the title compound (TFA salt, 25%). 1H NMR (600 MHz, DMSO-d6, 300 K) 1.15-1.37 (m, 3H), 1.22 (t, 7.1, 6H), 1.57 (bd, J 11.6, 1H), 1.67-1.74 (m, 2H), 1.84 (bd, J 11.6, 1H), 1.90-2.02 (m, 3H), 2.64-2.68 (m, 1H), 3.18 (q, J 7.1, 4H), 3.24-3.30 (m, 2H), 3.74 (bs, 2H), 3.86 (d, J 10.4, 1H), 3.95 (bd, J 15, 1H), 4.09 (d, J 10.8, 1H), 4.14 (d, J 10.4, 1H), 4.24 (bd, J 12.5, 1H), 4.28 (bd, J 12.5, 1H), 4.37 (d, J 10.8, 1H), 5.21 (bd, J 15, 1H), 7.20-7.22 (m, 3H), 7.48-7.51 (m, 1H), 7.69 (d, J 8.4, 1H), 7.90 (d, J 8.4, 1H), 8.55 (s, 1H); MS (ES+) m/z 516 (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 (91%)
  4. stirringthe mixture was stirred at 0° C. for 15 min
  5. stirringthe mixture was stirred at 70° C. for 2 h
  6. customAfter removal of the solvent EtOAc
  7. additionwas added
  8. washthe organic phase was washed with water and brine
  9. dry with materialdried over Na2SO4
  10. customthe solvent was removed in vacuo
  11. customwas hydrolysed with aq. 1N KOH in dioxane (75° C., 2 h) under degassed conditions
  12. customafter quenching at 0° C. with 1N HCl evaporation to dryness
  13. customgave a residue that
  14. customwas purified by RP-HPLC

Sources & evidence

ORD record
ord-667dfa0e249d486ba9d4ed8b5b7ad397
Source dataset
uspto-grants-2012_07
Patent number
US08232390B2

Reaction notes

Loading…