Triethylamine → 7-(1H-Pyrrolo[2,3-b]pyridin-5-yl)-1-(2-(tetrahydro-2h-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

HRID 717176Notes

Reaction equation

HRID 717176 reaction equation
[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[C:14]3=[N:15][C:16]([Sn](C)(C)C)=[CH:17][N:18]=[C:13]3[NH:12][CH2:11][C:10]2=[O:23])[CH2:3][CH2:2]1.Br[C:25]1[CH:26]=[C:27]2[CH:33]=[CH:32][NH:31][C:28]2=[N:29][CH:30]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C)C=O>[NH:31]1[C:28]2=[N:29][CH:30]=[C:25]([C:16]3[N:15]=[C:14]4[N:9]([CH2:8][CH2:7][CH:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)[C:10](=[O:23])[CH2:11][NH:12][C:13]4=[N:18][CH:17]=3)[CH:26]=[C:27]2[CH:33]=[CH:32]1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 80271Tri-o-tolylphosphineHCID 103079325-bromo-1H-pyrrolo[2,3-b]pyridineHCID 666067051-(2-(Tetrahydro-2H-pyran-4-yl)ethyl)-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

Product 1

HCID 594530677-(1H-Pyrrolo[2,3-b]pyridin-5-yl)-1-(2-(tetrahydro-2h-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-oneYield 11.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

1-(2-(Tetrahydro-2H-pyran-4-yl)ethyl)-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1.0 g, 2.352 mmol), 5-bromo-1H-pyrrolo[2,3-b]pyridine (0.556 g, 2.82 mmol), tris(dibenzylideneacetone)palladium(0) (0.237 g, 0.259 mmol), tri-o-tolylphosphine (0.158 g, 0.518 mmol) and triethylamine (0.984 mL, 7.06 mmol) were combined in a sealed tube, dimethylformamide (5 mL) was added. The atmosphere in the vessel was removed under vacuum and replaced with nitrogen gas. The reaction was heated to 100° C. for 1 h. After cooling to room temperature, the reaction mixture was filtered through Celite. The filter cake was washed with ethyl acetate. The wash and filtrate were combined and concentrated nearly to dryness. The resulting solid was dissolved in hot methanol, filtered through Celite and purified by reverse-phase preparative HPLC (5-80% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min). The clean fractions were collected, neutralized with ammonium hydroxide and concentrated to dryness. The solid obtained was filtered, washed with water and dried under high vacuum to yield the title compound (0.10 g, 0.264 mmol, 11.2% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 11.71 (br. s., 1H), 8.81 (s, 1H), 8.44 (s, 1H), 8.26 (s, 1H), 7.49 (d, J=10.54 Hz, 2H), 6.48 (br. s., 1H), 4.18 (s, 2H), 4.13 (t, J=6.44 Hz, 2H), 3.82 (d, J=12.89 Hz, 2H), 3.27 (t, J=11.13 Hz, 2H), 1.71 (d, J=12.49 Hz, 2H), 1.60 (br. s., 3H), 1.24 (d, 2H); MS (ESI) m/z 379.2 [M+1]+; mp 255-258° C.

Workup

  1. customThe atmosphere in the vessel was removed under vacuum
  2. temperatureAfter cooling to room temperature
  3. filtrationthe reaction mixture was filtered through Celite
  4. washThe filter cake was washed with ethyl acetate
  5. washThe wash
  6. concentrationconcentrated nearly to dryness
  7. dissolutionThe resulting solid was dissolved in hot methanol
  8. filtrationfiltered through Celite
  9. custompurified by reverse-phase preparative HPLC (5-80% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min)
  10. customThe clean fractions were collected
  11. concentrationconcentrated to dryness
  12. customThe solid obtained
  13. filtrationwas filtered
  14. washwashed with water
  15. customdried under high vacuum

Sources & evidence

ORD record
ord-f180bafa754945f79046f2a86492ffad
Source dataset
uspto-grants-2015_11
Patent number
US09193692B2

Reaction notes

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