Triethylamine → 7-[(6-Methylpyridin-3-yl)ethynyl]-1,2,3,4,5,6-hexahydro-1,4-methanoazepino[4,3-b]indole

HRID 1623059Notes

Reaction equation

HRID 1623059 reaction equation
C(N(CC)CC)C.[C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[N:14][CH:15]=1)#[CH:9].S([O-])([O-])(=O)=O.[Mg+2].Br[C:24]1[C:32]2[NH:31][C:30]3[CH2:33][CH:34]4[CH2:38][CH:37]([C:29]=3[C:28]=2[CH:27]=[CH:26][CH:25]=1)[NH:36][CH2:35]4>O1CCCC1.C(P([Pd]P(C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C.[Cu]I>[CH3:16][C:13]1[N:14]=[CH:15][C:10]([C:8]#[C:9][C:24]2[C:32]3[NH:31][C:30]4[CH2:33][CH:34]5[CH2:38][CH:37]([C:29]=4[C:28]=3[CH:27]=[CH:26][CH:25]=2)[NH:36][CH2:35]5)=[CH:11][CH:12]=1

Participants

8

Reactant 4

HCID 8471TriethylamineHCID 24083Sulfuric acid magnesium salt (1:1)HCID 6381975-Ethynyl-2-methylpyridineHCID 672388157-Bromo-1,2,3,4,5,6-hexahydro-1,4-methanoazepino[4,3-b]indole

Product 1

HCID 532526497-[(6-Methylpyridin-3-yl)ethynyl]-1,2,3,4,5,6-hexahydro-1,4-methanoazepino[4,3-b]indole

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178454917HCID 178454917, compoundCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
105 °C

Procedure

Triethylamine (1.0 mL) was added to a mixture of bis(tri-t-butylphosphino)palladium (7.4 mg, 0.014 mmol; Strem), 5-ethynyl-2-methylpyridine (51 mg, 0.43 mmol; International Publication No. WO2005090333), CuI (2.8 mg, 0.014 mmol; Aldrich), magnesium sulfate (2 mg, 0.014 mmol) and the product of Example 30A (80 mg, 0.29 mmol) in anhydrous tetrahydrofuran (1.0 mL). The mixture was purged with a nitrogen stream for 2 minutes, and then it was stirred in a sealed tube under nitrogen at 105° C. for 18 hours. The mixture was cooled to ambient temperature and filtered though a microfiber frit, rinsed with a minimal amount of methanol. The resulting solution was purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 60-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 1.91-1.97 (m, 1H), 2.01-2.12 (m, 1H), 2.56 (s, 3H), 2.85 (dd, J=16.9, 2.3 Hz, 1H), 3.01-3.09 (m, 1H), 3.11-3.20 (m, 2H), 3.46 (t, J=3.7 Hz, 1H), 3.81-3.94 (m, 1H), 6.96-7.02 (m, 1H), 7.21 (dd, J=7.3, 0.9 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 7.50 (dd, J=7.9, 0.9 Hz, 1H), 7.93 (dd, J=7.9, 2.1 Hz, 1H), 8.67 (d, J=1.8 Hz, 1H); MS (ESI+) m/z 314 (M+H)+.

Workup

  1. customThe mixture was purged with a nitrogen stream for 2 minutes
  2. temperatureThe mixture was cooled to ambient temperature
  3. filtrationfiltered though a microfiber frit
  4. washrinsed with a minimal amount of methanol
  5. customThe resulting solution was purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 60-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)]

Sources & evidence

ORD record
ord-0ebcfd0c341c461cbe65afba34c17f20
Source dataset
uspto-grants-2014_07
Patent number
US08778959B2

Reaction notes

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