Potassium Iodide → ethyl (10R,15S)-3-oxo-1,4,12-triazatetracyclo[7.6.1.05,16.010,15]hexadeca-5,7,9(16)-triene-12-carboxylate

HRID 1624925Notes

Reaction equation

HRID 1624925 reaction equation
Br[C:2]1[C:10]2[NH:9][C@H:8]3[CH2:11][CH2:12][N:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][C@H:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][C:22]([NH2:24])=[O:23].[I-].[K+].C(N(C(C)C)CC)(C)C.CNC(=O)CCl.C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu](I)I.O1CCOCC1>[O:23]=[C:22]1[CH2:21][N:9]2[C@H:8]3[CH2:11][CH2:12][N:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][C@H:7]3[C:6]3[C:10]2=[C:2]([CH:3]=[CH:4][CH:5]=3)[NH:24]1

Participants

10

Reactant 7

HCID 4875Potassium IodideHCID 6580ChloroacetamideHCID 8070N,N'-DimethylethylenediamineHCID 11430Potassium CarbonateHCID 667732-chloro-N-methylacetamideHCID 81531Diisopropylethylamine2×HCID 59317960ethyl (4aS,9bR)-6-bromo-1H,2H,3H,4H,4aH,5H,9bH-pyrido(4,3-b)indole-2-carboxylate

Product 1

HCID 20578971ethyl (10R,15S)-3-oxo-1,4,12-triazatetracyclo[7.6.1.05,16.010,15]hexadeca-5,7,9(16)-triene-12-carboxylate

Reagents, catalysts & solvents 2

HCID 83717Copper iodideCatalystHCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
103 °C

Procedure

Alternative to Example 5 above, (6bR,10aS)-ethyl 3,6b,9,10,10a-hexahydro-3-methyl-2-oxo-1H-pyrido[3′,4′:4,5]-pyrrolo[1,2,3-de]quinoxaline-8-carboxylate may also be made in a one pot method starting from Compound of Formula 1D. A 2 liter 4 neck round bottom flask is equipped with a mechanical stirrer, reflux condenser, N2 inlet, teflon covered K-type temperature probe with a controller, and a heating mantle. To the flask is charged (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate (250 g, 769 mmol), chloroacetamide (124 g, 1153 mmol, 1.5 equiv), potassium iodide (191.5 g, 1160 mmol, 1.5 equiv), diisopropyl ethylamine (266 mL, 1531 mmol, 2.0 equiv), and dioxane (625 mL). The reaction is heated to reflux temperature of about 103° C. until less than 3% of the starting substrate is observed by HPLC (about 48 hours). Additional charge of N-methyl chloroacetamide and diisopropyl ethylamine maybe necessary. The reaction is then cooled to ca. 80° C., and at this temperature copper iodide (29.2 g, 153.8 mmol, 0.2 equiv), potassium carbonate (232.5 g, 1682 mmol, 2.2 equiv), dimethylethylene diamine (49.6 mL, 461 mmol, 0.6 equiv), and additional dioxane (375 mL) is added. The reaction is then re-heated to reflux and is monitored by HPLC. Reflux occurs at ca. 103° C. The reaction is monitored by HPLC.

Workup

  1. temperaturereflux condenser, N2 inlet
  2. temperatureThe reaction is heated
  3. customis observed by HPLC (about 48 hours)
  4. temperatureThe reaction is then cooled to ca. 80° C.
  5. temperatureThe reaction is then re-heated
  6. temperatureto reflux
  7. temperatureReflux
  8. customoccurs at ca. 103° C

Sources & evidence

ORD record
ord-cca6c1525efd4aecbe2a2ac167653e4f
Source dataset
uspto-grants-2014_07
Patent number
US08779139B2

Reaction notes

Loading…