Cesium carbonate → 5-(1-Ethyl-piperidin-4-yloxy)-3-methyl-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile

HRID 60333Notes

Reaction equation

HRID 60333 reaction equation
C1(S([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:28]#[N:29])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:26][CH3:27])[CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:30]=[C:31](Br)[CH:32]=[N:33][C:11]2=3)(=O)=O)C=CC=CC=1.[CH3:35]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH2:26]([N:23]1[CH2:24][CH2:25][CH:20]([O:19][C:18]2[C:13]3[C:12]4[CH:30]=[C:31]([CH3:35])[CH:32]=[N:33][C:11]=4[NH:10][C:14]=3[CH:15]=[N:16][C:17]=2[C:28]#[N:29])[CH2:21][CH2:22]1)[CH3:27]

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 574072TrimethylboroxineHCID 582668389-Benzenesulfonyl-3-bromo-5-(1-ethyl-piperidin-4-yloxy)-9H-dipyrido[2,3-b:4',3'-d]pyrrole-6-carbonitrile

Product 1

HCID 583651685-(1-Ethyl-piperidin-4-yloxy)-3-methyl-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrileYield 52%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 9-benzenesulfonyl-3-bromo-5-(1-ethyl-piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (215 mg, 0.40 mmol), trimethylboroxine (167 μL, 1.2 mmol), cesium carbonate (156 mg, 0.48 mmol) and tetrakis(triphenyl-phosphine)palladium(0) (96 mg, 0.04 mmol) in dioxane (2.0 mL) was degassed with argon and heated under microwave irradiation at 100° C. for 90 minutes. The reaction mixture was allowed to cool to ambient temperature, diluted with saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (3×10 mL). The combined organic phase was washed with brine (2×10 mL) and concentrated in-vacuo. The resultant residue was diluted with THF (10 mL), 1N aqueous potassium hydroxide (1 mL) added and the reaction mixture was then heated at 50° C. for 1 hour. The solvent was evaporated in-vacuo and the resultant residue was purified by chromatography (silica, 2 g column, Si-SPE, 0-10% 2-propanol in dichloromethane). The appropriate fractions were combined and evaporated in-vacuo and the resultant residue triturated with pentane (2×2 mL) to afford the title compound as an off-white solid (69 mg, 52%). LCMS (Method A): RT=2.46 min, M+H+=336.2. 1H NMR (400 MHz, CD3OD): 8.71 (s, 1H), 8.52 (dd, J=2.1, 0.7 Hz, 1H), 8.47 (dd, J=2.1, 0.9 Hz, 1H), 4.91-4.88 (m, 1H), 3.02-2.99 (m, 2H), 2.57 (s, 3H), 2.50 (q, J=7.2 Hz, 2H), 2.26-2.19 (m, 4H), 2.12-2.11 (m, 2H), 1.13 (t, J=7.2 Hz, 3H).

Workup

  1. customwas degassed with argon
  2. temperatureto cool to ambient temperature
  3. additiondiluted with saturated aqueous ammonium chloride (10 mL)
  4. extractionextracted with dichloromethane (3×10 mL)
  5. washThe combined organic phase was washed with brine (2×10 mL)
  6. concentrationconcentrated in-vacuo
  7. additionThe resultant residue was diluted with THF (10 mL), 1N aqueous potassium hydroxide (1 mL)
  8. additionadded
  9. temperaturethe reaction mixture was then heated at 50° C. for 1 hour
  10. customThe solvent was evaporated in-vacuo
  11. customthe resultant residue was purified by chromatography (silica, 2 g column, Si-SPE, 0-10% 2-propanol in dichloromethane)
  12. customevaporated in-vacuo
  13. customthe resultant residue triturated with pentane (2×2 mL)

Sources & evidence

ORD record
ord-824f3c6438c94f46a7197e704284dc08
Source dataset
uspto-grants-2016_09
Patent number
US09440976B2

Reaction notes

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