Isopropylamine → 14′-Cyclohexyl-1-(1-methylethyl)spiro[azetidine-3,7′(8′H)-[6H]indolo[1,2-e][1,5]benzoxazocine]-11′-carboxylic acid

HRID 1518219Notes

Reaction equation

HRID 1518219 reaction equation
O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[CH:28]1([C:34]2[C:35]3[CH:36]=[CH:37][C:38]([C:57]([O:59]C)=[O:58])=[CH:39][C:40]=3[N:41]3[C:48]=2[C:47]2[CH:49]=[CH:50][CH:51]=[CH:52][C:46]=2[O:45][CH2:44][C:43]([CH2:55]O)([CH2:53]O)[CH2:42]3)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.CC[N:63](C(C)C)[CH:64]([CH3:66])[CH3:65].C(N)(C)C>CO.C1COCC1.CC#N.CCOC(C)=O>[CH:28]1([C:34]2[C:35]3[CH:36]=[CH:37][C:38]([C:57]([OH:59])=[O:58])=[CH:39][C:40]=3[N:41]3[C:48]=2[C:47]2[CH:49]=[CH:50][CH:51]=[CH:52][C:46]=2[O:45][CH2:44][C:43]2([CH2:53][N:63]([CH:64]([CH3:66])[CH3:65])[CH2:55]2)[CH2:42]3)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1

Participants

9

Reactant 5

HCID 6363IsopropylamineHCID 67749Trifluoromethanesulfonic anhydrideHCID 81531Diisopropylethylamine2×HCID 521998p-Toluenesulfonic acid monohydrateHCID 67345199HCID 67345199, compound

Product 1

HCID 2487227414′-Cyclohexyl-1-(1-methylethyl)spiro[azetidine-3,7′(8′H)-[6H]indolo[1,2-e][1,5]benzoxazocine]-11′-carboxylic acidYield 4%

Reagents, catalysts & solvents 3

HCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolventHCID 21899815MeOH tetrahydrofuranSolvent

Procedure

A catalytic amount of para-toluenesulfonic acid monohydrate was added to a suspension of methyl 14′-cyclohexyl-2,2-dimethylspiro[1,3-dioxane-5,7′-indolo[1,2e][1,5]benzoxazocine]-11′-carboxylate in MeOH/THF 1:2 (0.03 M), and the solution was stirred for 3 h at RT. Filtration over a pad of neutral alumina with EtOAc 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). Triflic anhydride (2.8 eq) was added at 0° C. to a solution of methyl 14-cyclohexyl-7,7-bis(hydroxymethyl)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate in dry MeCN (0.05M), DIPEA (3.0 eq) was added and the mixture was stirred for 15 min at 0° C., then further 3.0 eq of DIPEA were added, followed by iPrNH2 (2 eq). The mixture was transferred into a closed vessel and stirring was continued at 70° C. for 4 h. 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 aqueous 1N KOH in dioxane (65° C., overnight); evaporation to dryness gave a residue that was purified by RP-HPLC to afford the title compound (4%). 1H NMR (300 MHz, DMSO-d6, 330 K) δ 8.50 (s, 1H), 7.87 (d, 1H, J 8.3), 7.70 (d, 1H, J 8.3), 7.51-7.46 (m, 1H), 7.24-7.15 (m, 3H), 5.16 (b.d, 1H, J 15.9), 4.28 (d, 1H, J 12.7), 4.20 (d, 1H, J 12.7), 4.1-3.5 (m, 6H), 2.75-2.66 (m, 1H), 2.01-1.58 (m, 7H), 1.39-1.17 (m, 9H); MS (ES+) m/z 459 (M+H)+.

Workup

  1. filtrationFiltration over a pad of neutral alumina with EtOAc
  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. additionwas added
  5. stirringthe mixture was stirred for 15 min at 0° C.
  6. customThe mixture was transferred into a closed vessel
  7. stirringstirring
  8. waitwas continued at 70° C. for 4 h
  9. washthe organic phase was washed with water and brine
  10. dry with materialdried over Na2SO4
  11. customthe solvent was removed in vacuo
  12. customwas hydrolysed with aqueous 1N KOH in dioxane (65° C., overnight)
  13. customevaporation to dryness
  14. customgave a residue that
  15. customwas purified by RP-HPLC

Sources & evidence

ORD record
ord-3ec543dd7a3d40278dfb60fd859e91ae
Source dataset
uspto-grants-2012_07
Patent number
US08232390B2

Reaction notes

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