Methanol → 6-{[{2-[(tert-butoxycarbonyl)(methyl)amino]ethyl}(methyl)amino]methyl}-13-cyclohexyl-5-methyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-10-carboxylic acid

HRID 1669425Notes

Reaction equation

HRID 1669425 reaction equation
[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([O:30]C)=[O:29])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]([CH3:25])[CH:16]([CH:26]=O)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][NH:33][CH2:34][CH2:35][NH:36][CH3:37].[BH3-]C#N.[Na+].[OH-:42].[K+].[CH3:44][OH:45]>CCOC(C)=O.CC(O)=O>[C:1]([O:42][C:44]([N:33]([CH3:32])[CH2:34][CH2:35][N:36]([CH2:26][CH:16]1[CH2:15][N:14]2[C:13]3[CH:12]=[C:11]([C:28]([OH:30])=[O:29])[CH:10]=[CH:9][C:8]=3[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:20]2[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]1[CH3:25])[CH3:37])=[O:45])([CH3:7])([CH3:6])[CH3:2]

Participants

8

Reactant 5

HCID 887MethanolHCID 8070N,N'-DimethylethylenediamineHCID 14797Potassium HydroxideHCID 5003444Sodium cyanoborohydrideHCID 86627899Methyl 13-cyclohexyl-6-formyl-5-methyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-10-carboxylate

Product 1

HCID 673439786-{[{2-[(tert-butoxycarbonyl)(methyl)amino]ethyl}(methyl)amino]methyl}-13-cyclohexyl-5-methyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-10-carboxylic acid

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

Methyl 13-cyclohexyl-6-formyl-5-methyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-10-carboxylate was dissolved in MeOH (0.09M) and HOAc was added. N,N′-dimethylethylendiamine (4 eq) was added and the mixture was stirred for 5 min. NaCNBH3 (1.5 eq) was added and the mixture was stirred overnight. All volatiles were then evaporated in vacuo and the residual material was dissolved in EtOAc. The solution was extracted with sat. aq. NH4Cl, sat. aq. NaHCO3 and brine. After drying over Na2SO4 all volatiles were evaporated in vacuo. The crude residue of methyl 13-cyclohexyl-5-methyl-6-({methyl[2-(methylamino)ethyl]amino}methyl)-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-10-carboxylate was dissolved in dioxane (0.05M) and di-tert-butyl dicarbonate2O (2 eq) was added. The mixture was stirred for 1 h. All volatiles were then evaporated in vacuo and the residual material was taken up in EtOAc. The solution was extracted with sat. aq. NH4Cl, sat. aq. NaHCO3 and with brine. After drying over Na2SO4 all volatiles were evaporated in vacuo. The residual material was filtered through a pad of silica gel (PE:EtOAc, 7:3). After evaporation of the solvents, the crude mixture of methyl 6-{[{2-[(tert-butoxycarbonyl)(methyl)amino]ethyl}-(methyl)amino]methyl}-13-cyclohexyl-5-methyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-10-carboxylate was dissolved in dioxane (0.05M) and 1M KOH solution (2 eq) was added. The mixture was warmed to 60° C. After 12 h, EtOAc was added and the mixture was extracted with 10% aqueous citric acid solution and brine. After drying the organic phase over Na2SO4 all volatiles were evaporated in vacuo. The residual solid (6-{[{2-[(tert-butoxycarbonyl)(methyl)amino]ethyl}-(methyl)amino]methyl}-13-cyclohexyl-5-methyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-10-carboxylic acid) was used without further purification in the next reaction (67% over 3 steps). (ES+) m/z 575 (M+H)+.

Workup

  1. stirringthe mixture was stirred overnight
  2. customAll volatiles were then evaporated in vacuo
  3. dissolutionthe residual material was dissolved in EtOAc
  4. extractionThe solution was extracted with sat. aq. NH4Cl, sat. aq. NaHCO3 and brine
  5. dry with materialAfter drying over Na2SO4 all volatiles
  6. customwere evaporated in vacuo
  7. dissolutionThe crude residue of methyl 13-cyclohexyl-5-methyl-6-({methyl[2-(methylamino)ethyl]amino}methyl)-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-10-carboxylate was dissolved in dioxane (0.05M)
  8. additiondi-tert-butyl dicarbonate2O (2 eq) was added
  9. stirringThe mixture was stirred for 1 h
  10. customAll volatiles were then evaporated in vacuo
  11. extractionThe solution was extracted with sat. aq. NH4Cl, sat. aq. NaHCO3 and with brine
  12. dry with materialAfter drying over Na2SO4 all volatiles
  13. customwere evaporated in vacuo
  14. filtrationThe residual material was filtered through a pad of silica gel (PE:EtOAc, 7:3)
  15. customAfter evaporation of the solvents
  16. additionthe crude mixture of methyl 6-{[{2-[(tert-butoxycarbonyl)(methyl)amino]ethyl}-(methyl)amino]methyl}-13-cyclohexyl-5-methyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-10-carboxylate
  17. dissolutionwas dissolved in dioxane (0.05M)
  18. waitAfter 12 h
  19. extractionthe mixture was extracted with 10% aqueous citric acid solution and brine
  20. dry with materialAfter drying the organic phase over Na2SO4 all volatiles
  21. customwere evaporated in vacuo
  22. customThe residual solid (6-{[{2-[(tert-butoxycarbonyl)(methyl)amino]ethyl}-(methyl)amino]methyl}-13-cyclohexyl-5-methyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-10-carboxylic acid) was used without further purification in the next reaction (67% over 3 steps)

Sources & evidence

ORD record
ord-cc0666f2072b48be890949b45ab04072
Source dataset
uspto-grants-2011_08
Patent number
US07989438B2

Reaction notes

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