Acetic Anhydride → 1-{2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-3-[(propan-2-yl)amino]-5H,6H,7H,8H-pyrido[3,4-b]pyrazin-6-yl}ethan-1-one

HRID 713301Notes

Reaction equation

HRID 713301 reaction equation
[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[C:13]3[CH:24]=[CH:23][N:22]=[CH:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:7][CH2:6]1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>O1CCOCC1.CC(C)=O.[Pd]>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]2[N:12]=[C:13]3[CH2:24][CH2:23][N:22]([C:30](=[O:32])[CH3:31])[CH2:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:9][CH2:10]1

Participants

6

Reactant 2

HCID 7918Acetic Anhydride2×HCID 90037662HCID 90037662, compound

Product 1

HCID 918107711-{2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-3-[(propan-2-yl)amino]-5H,6H,7H,8H-pyrido[3,4-b]pyrazin-6-yl}ethan-1-oneYield 51.2%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 180AcetoneSolventHCID 312751,4-DioxaneSolvent

Procedure

A mixture of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropylpyrido[3,4-b]pyrazin-3-amine (100 mg, 0.250 mmol), acetic anhydride (0.09 mL, 1.00 mmol) and 10% Pd/C (9.0 mg) in a mixture of dioxane (2.5 mL) and acetone (1.5 mL) was stirred at room temperature for 24 h. Then, 4.0 equivalents of acetic anhydride was added and stirring was continued for 2 days. After filtration, the reaction solution was quenched with saturated NaHCO3 and the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organic phase was dried with anhydrous Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography using a 30% to 100% gradient of EtOAc in heptane gave the title compound (57 mg, 51%) as a white solid. 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.23 (d, J=6.6 Hz, 3.3H), 1.24 (d, J=6.6 Hz, 2.7H), 1.93 (m, 2H), 2.11 (m, 2H), 2.18 (s, 1.3H), 2.20 (s, 1.7H), 2.71 (t, J=6.1 Hz, 0.9H), 2.80 (t, J=6.1 Hz, 1.1H), 2.95 (m, 2H), 3.34 (m, 2H), 3.79 (t, J=5.9 Hz, 1.1H), 3.84 (t, J=6.1 Hz, 0.9H), 4.15 (m, 1H), 4.44 (tt, J=7.5, 3.7 Hz, 1H), 4.53 (s, 0.9H), 4.54 (s, 1.1H), 6.86 (m, 1H), 6.97 (ddd, J=11.2, 8.5, 3.2 Hz, 1H), 7.16 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 446.00.

Workup

  1. stirringstirring
  2. waitwas continued for 2 days
  3. filtrationAfter filtration
  4. customthe reaction solution was quenched with saturated NaHCO3
  5. extractionthe aqueous layer was extracted with ethyl acetate (3×5 mL)
  6. dry with materialThe combined organic phase was dried with anhydrous Na2SO4
  7. concentrationconcentrated under vacuum
  8. customPurification by silica gel column chromatography

Sources & evidence

ORD record
ord-07f9cc9104b04d93a07ca77573fd4ecd
Source dataset
uspto-grants-2015_11
Patent number
US09181249B2

Reaction notes

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