Hydrochloric Acid → tert-butyl 7-bromo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate

HRID 1020522

Reaction equation

HRID 1020522 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]([NH:8]N)[CH:5]=[CH:6][CH:7]=1.[C:10]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].Cl.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.C(N(CC)CC)C>C(O)C.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:19]3[CH2:18][N:17]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:22][CH2:21][C:20]=3[NH:8][C:4]=2[CH:3]=1

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 33758(3-Bromophenyl)hydrazineHCID 90495Di-tert-butyl dicarbonateHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylate

Product 1

HCID 57950374tert-butyl 7-bromo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylateYield 42%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 702EthanolSolvent

Procedure

3-Bromophenylhydrazine (40.0 g, 0.179 mol) and N-Boc-4-oxo-piperidine (35.4 g, 0.179 mol) were dissolved in ethanol (368 mL), and conc. HCl (72 mL) was added. The reaction mixture was then heated to reflux for 18 h, concentrated and basified using 10% NH4OH in methanol (10%, 100 mL). The solvent was removed, and the residue was suspended in CH2Cl2 (1.2 L). Boc2O (39.2 g, 0.179 mol) followed by DMAP (195 mg, 1.6 mmol) and triethylamine (46.4 mL, 0.358 mol) were then added, and the reaction progressed at room temperature for 18 h. The mixture was washed with 0.5 N HCl, and the organic phase was removed, dried over Na2SO4, filtered and concentrated to dryness. The resulting mixture of regioisomers was purified by flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 80:20 to 50:50 then 25:75) to give the more polar title compound (26.2 g, 42%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.16 (br s, 1H), 7.42 (s, 1H), 7.28 (d, J=8.1 Hz, 1H, partially masked by solvent), 7.18 (d, J=8.1 Hz, 1H), 4.60 (s, 2H), 3.80 (t, J=5.5 Hz, 2H), 2.79 (t, J=5.6 Hz, 2H), 1.51 (s, 9H).

Workup

  1. temperatureThe reaction mixture was then heated
  2. temperatureto reflux for 18 h
  3. concentrationconcentrated
  4. customThe solvent was removed
  5. additionwere then added
  6. washThe mixture was washed with 0.5 N HCl
  7. customthe organic phase was removed
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated to dryness
  11. additionThe resulting mixture of regioisomers
  12. customwas purified by flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 80:20 to 50:50

Sources & evidence

ORD record
ord-5b620c905833412783bb4750881d852f
Source dataset
uspto-grants-2014_05
Patent number
US08716308B2

Linked notes

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