Glyoxylic Acid → tert-Butyl 7-bromo-6-fluoro-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

HRID 930786Notes

Reaction equation

HRID 930786 reaction equation
C(O)(=O)C=O.BrC1C=C2C(C(CCN)=CN2)=CC=1F.[OH-].[Na+].[Br:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]3[CH2:35][CH2:34][NH:33][CH2:32][C:28]=3[NH:29]2)=[CH:25][C:24]=1[F:36].BrC1C2NC3CCNCC=3C=2C=CC=1F.[C:52](=O)([O:58]C(C)(C)C)[O:53][C:54]([CH3:57])([CH3:56])[CH3:55]>Cl.ClCCl.CN(C1C=CN=CC=1)C>[Br:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]3[CH2:35][CH2:34][N:33]([C:52]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:58])[CH2:32][C:28]=3[NH:29]2)=[CH:25][C:24]=1[F:36]

Participants

10

Reactant 6

HCID 760Glyoxylic AcidHCID 14798Sodium Hydroxide3×HCID 10219638Carbonic acid, bis(1,1-dimethylethyl) esterHCID 57950350HCID 57950350, compoundHCID 68657467HCID 68657467, compoundHCID 68657570HCID 68657570, compound

Product 1

HCID 57950329tert-Butyl 7-bromo-6-fluoro-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylateYield 12%

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 313Hydrochloric AcidSolvent2×HCID 6344DichloromethaneSolvent

Procedure

Glyoxylic acid (8.6 g, 95 mmol) was added to a solution of 2-(6-bromo-5-fluoro-1H-indol-3-yl)ethanamine (8.1 g 31 mmol) in 2 N HCl (150 ml), and the pH of the resulting solution was adjusted to pH 3.5 with 6 N NaOH solution. The reaction mixture was stirred at ambient temperature for 18 h. The solution was adjusted to pH 5.5 with 6 N NaOH solution. The resulting precipitate was collected by filtration and dried under vacuum to afford a yellow solid. The yellow solid was suspended in 2 N HCl (100 mL), and the resulting mixture was stirred at reflux for 4.5 h. The reaction mixture was cooled to ambient temperature and was adjusted to pH 10 by addition of 2 N sodium hydroxide solution. The resulting precipitate was collected by filtration and dried under vacuum to afford a crude mixture of 7-bromo-6-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole and 6-bromo-7-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2.0 g, 23%) as a yellow solid. The mixture (1.9 g, 7.1 mmol) was suspended in dichloromethane (100 mL) and di-tert-butyl carbonate (1.85 g, 8.7 mmol) was added, followed by addition of DMAP (100 mg, 0.82 mmol). The reaction mixture was stirred at ambient temperature for 18 h and concentrated under vacuum. The residue was purified twice by column chromatography (silica gel, hexanes/ethyl acetate, 0:1 to 1:1) to afford the title compound (300 mg, 12%) as a pale yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.46 (d, J=5.7 Hz, 1H), 7.18 (d, J=9.0 Hz, 1H), 4.61 (s, 2H), 3.75 (br m, 2H), 2.73 (br m, 2H), 1.56 (s, 9H); ESI MS m/z 369 [M+H]+.

Workup

  1. filtrationThe resulting precipitate was collected by filtration
  2. customdried under vacuum
  3. customto afford a yellow solid
  4. stirringthe resulting mixture was stirred
  5. temperatureat reflux for 4.5 h
  6. temperatureThe reaction mixture was cooled to ambient temperature
  7. filtrationThe resulting precipitate was collected by filtration
  8. customdried under vacuum
  9. customto afford a crude
  10. stirringThe reaction mixture was stirred at ambient temperature for 18 h
  11. concentrationconcentrated under vacuum
  12. customThe residue was purified twice by column chromatography (silica gel, hexanes/ethyl acetate, 0:1 to 1:1)

Sources & evidence

ORD record
ord-a1909d50d98c4ccd80b7d31553d154a0
Source dataset
uspto-grants-2016_03
Patent number
US09296743B2

Reaction notes

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