Hydrochloric Acid → methyl 3-benzyl-1,2,3,3a,4,5-hexahydro-4-(3-hydroxypropyl)-7H-pyrrolo(2,3-d)carbazole-6-carboxylate

HRID 330600Notes

Reaction equation

HRID 330600 reaction equation
[CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4][NH:3][CH2:2]1.Cl.O[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1.[NH4+].[OH-].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CO.C1COCC1.CO.C(Cl)Cl.O>[CH2:29]([N:3]1[CH:21]2[CH:26]([CH2:25][CH2:24][CH2:23][OH:22])[CH2:4][C:5]([C:15]([O:17][CH3:18])=[O:16])=[C:6]3[NH:7][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:14]23[CH2:1][CH2:2]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 7498Benzyl BromideHCID 14923Ammonium HydroxideHCID 1365052-HydroxytetrahydropyranHCID 11021133Methyl 1,2,3,4,5,6-hexahydroazepino(4,5-b)indole-5-carboxylate

Product 1

HCID 13856926methyl 3-benzyl-1,2,3,3a,4,5-hexahydro-4-(3-hydroxypropyl)-7H-pyrrolo(2,3-d)carbazole-6-carboxylateYield 68.1%

Reagents, catalysts & solvents 4

HCID 887MethanolSolvent2×HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 21226129Dichloromethane methanolSolvent

Conditions

Temperature
20 °C

Procedure

To methyl 1,2,3,4,5,6-hexahydroazepino(4,5-b)indole-5-carboxylate (5.0 g, 20 mmol) stirring in methanol (25 mL) was added enough methanol saturated with HCl to turn moist universal pH paper red. The methanol was evaporated at reduced pressure and to the residue was added H2O (50 mL) and 2-hydroxytetrahydropyran (2.2 g, 22 mmol) and the mixture was allowed to stir at 20° C. overnight. TLC (SiO2, 7.5% methanol/CH2Cl2,) of the mixture showed the formation of two products which were methyl 1,2,4,6-tetrahydro-11-β(4-hydroxybutyl)-3,10b-methanoazepino (4,5-b)indole-5-carboxylate and methyl 1,2,4,6-tetrahydro-11-α (4-hydroxybutyl)-3,10b-methanoazepino (4,5-b)indole-5-carboxylate (Rf 0.68 and 0.76, CAS, blue). The reaction mixture was basified (NH4OH), 10% (aq) and extracted three times with CH2Cl2. The organic extracts were dried (Na2SO4) and concentrated to a residue, which was immediately dissolved in THF (100 mL). To the THF solution was added benzyl bromide (2.5 mL, 21 mmol) and then the solution was heated to reflux and monitored by TLC until conversion to the mixture of 3-benzyl 1,2,4,6-tetrahydro-11-β(4-hydroxybutyl)-5-methoxycarbonyl-3,10b-methanoazepino (4,5-b)indolium bromide and 3-benzyl-1,2,4,6-tetrahydro-11-α(4'-hydroxybutyl)-5-methoxycarbonyl-3,10b-methanoazepino (4,5-b)indolium bromide (about 2h) was completed. At this point the THF was evaporated and replaced with methanol (100 mL) and diisopropyl ethyl amine (5.3 mL). Reflux was restarted until TLC showed complete disappearance of the above mixture of compounds. The methanol was evaporated and the residue chromatographed (SiO2, 5% methanol/CH2Cl2) to yield 5.7 g (67%) of methyl 3-benzyl-1,2,3,3a,4,5-hexahydro-4(3-hydroxy-propyl)-7H-pyrrolo(2,3-d)carbazole-6-carboxylate as a gum;TLC (SiO2, 7.5% methanol/CH2Cl2) Rf 0.86 (CAS, blue).

Workup

  1. customThe methanol was evaporated at reduced pressure and to the residue
  2. extractionextracted three times with CH2Cl2
  3. dry with materialThe organic extracts were dried (Na2SO4)
  4. concentrationconcentrated to a residue, which
  5. dissolutionwas immediately dissolved in THF (100 mL)
  6. temperaturethe solution was heated
  7. temperatureto reflux
  8. customAt this point the THF was evaporated
  9. temperatureReflux
  10. additiondisappearance of the above mixture of compounds
  11. customThe methanol was evaporated
  12. customthe residue chromatographed (SiO2, 5% methanol/CH2Cl2)

Sources & evidence

ORD record
ord-0eaaa733973248888ab07cb839af421a
Source dataset
uspto-grants-1990_01
Patent number
US04897477

Reaction notes

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