Acetic Anhydride → 1-(3-(cyclobutylamino)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one

HRID 713361Notes

Reaction equation

HRID 713361 reaction equation
[CH:1]1([NH:5][C:6]2[N:11]=[C:10]3[CH:12]=[N:13][CH:14]=[CH:15][C:9]3=[N:8][C:7]=2[N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[CH2:18][CH2:17]2)[CH2:4][CH2:3][CH2:2]1.[CH3:31][C:32](OC(C)=O)=[O:33]>CC(C)=O.O1CCOCC1.[Pd]>[CH:1]1([NH:5][C:6]2[N:11]=[C:10]3[CH2:12][N:13]([C:32](=[O:33])[CH3:31])[CH2:14][CH2:15][C:9]3=[N:8][C:7]=2[N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[CH2:18][CH2:17]2)[CH2:2][CH2:3][CH2:4]1

Participants

6

Reactant 2

HCID 7918Acetic AnhydrideHCID 73295084N-cyclobutyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-3-amine

Product 1

HCID 1181591611-(3-(cyclobutylamino)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-oneYield 45.7%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 180AcetoneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of N-cyclobutyl-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-3-amine (12.0 g, 29.2 mmol) in acetone (200 mL) and dioxane (300 mL) was added Ac2O (30 mL, 318 mmol) and Pd/C (1.80 g, 16.91 mmol). The reaction was then stirred at 60° C. under H2 atmosphere (345 kPa) for 72 h. Then the mixture was filtered through a pad of Celite™, washing with EtOAc. The reaction solution was diluted with EtOAc (50 mL) and poured into saturated aqueous NaHCO3 (50 mL), then washed with brine (2×30 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was recrystallized with PEEtOAc, lyophilized and washed with PEEtOAc (5:1) to give pure title compound (6.1 g). 1H NMR (500 MHz, DMSO-d6, mixture of rotamers) δ ppm 1.57-1.74 (m, 2H), 1.85-1.95 (m, 2H), 1.97-2.08 (m, 4H), 2.08 (s, 1.3H), 2.09 (s, 1.7H), 2.19-2.30 (m, 2H), 2.58 (t, J=5.9 Hz, 0.9H), 2.71 (t, J=5.9 Hz, 1.1H), 2.88 (t, J=10.5 Hz, 2H), 3.23-3.33 (m, 2H), 3.70 (dt, J=11.7, 5.9 Hz, 2H), 4.32-4.47 (m, 3H), 4.52 (tt, J=8.1, 3.8 Hz, 1H), 6.05 (d, J=7.8 Hz, 0.4H), 6.08 (d, J=8.3 Hz, 0.6H 6.96-7.07 (m, 1H), 7.24-7.36 (m, 2H); ESI-MS m/z [M+H]+ 458.00.

Workup

  1. filtrationThen the mixture was filtered through a pad of Celite™
  2. washwashing with EtOAc
  3. additionThe reaction solution was diluted with EtOAc (50 mL)
  4. additionpoured into saturated aqueous NaHCO3 (50 mL)
  5. washwashed with brine (2×30 mL)
  6. dry with materialThe organic layer was dried over Na2SO4
  7. concentrationconcentrated in vacuo
  8. customThe crude product was recrystallized with PEEtOAc
  9. washwashed with PEEtOAc (5:1)

Sources & evidence

ORD record
ord-502fe3c82bff45e5a811b98f6697cf07
Source dataset
uspto-grants-2015_11
Patent number
US09181249B2

Reaction notes

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