Dimethylformamide → 7-(8-Chloro-3-(3-methylenecyclobutyl)imidazo[1,5-a]pyrazin-1-yl)-2-phenylquinoline

HRID 244150Notes

Reaction equation

HRID 244150 reaction equation
[Cl:1][C:2]1[C:3]([CH:8]([C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[CH:22][C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[N:24]3)=[CH:19][CH:18]=2)[NH:9][C:10]([CH:12]2[CH2:15][C:14](=[CH2:16])[CH2:13]2)=O)=[N:4][CH:5]=[CH:6][N:7]=1.CN(C=O)C>O=P(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([CH:12]3[CH2:15][C:14](=[CH2:16])[CH2:13]3)=[N:9][C:8]=2[C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[CH:22][C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[N:24]3)=[CH:19][CH:18]=2)[CH:5]=[CH:6][N:7]=1

Participants

4

Reactant 2

HCID 6228DimethylformamideHCID 53629057N-((3-chloropyrazin-2-yl)(2-phenylquinolin-7-yl)methyl)-3-methylenecyclobutanecarboxamide

Product 1

HCID 536290387-(8-Chloro-3-(3-methylenecyclobutyl)imidazo[1,5-a]pyrazin-1-yl)-2-phenylquinoline

Reagents, catalysts & solvents 1

HCID 24813Phosphorus oxychlorideSolvent

Conditions

Temperature
55 °C

Procedure

N-[(3-Chloropyrazin-2-yl)(2-phenylquinolin-7-yl)methyl]-3 methylenecyclobutanecarboxamide (0.02 mmol, 10 g) was dissolved in 150 mL POCl3 in a 250 mL rbf, charged with 0.1 mL DMF and heated to 55° C. under a consistent N2 flow for 1 h (the reaction was vented with a needle). The excess POCl3 was removed under reduced pressure and the residue was quenched with 2 N NH3 in isopropanol (250 mL) at 0° C. and water. The aqueous layer was washed with DCM (100 mL×2) and the combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (flash column) eluting with 20-50% EtOAc in hexane. Concentration in vacuo of the product-rich fractions afforded the desired product as yellow solid; MS (ES, Pos.): m/z 423 (100) [MH+]; 1H NMR (CDCl3, 400 MHz) δ 3.28-3.31 (m, 2H), 3.39-3.42 (m, 2H), 3.85-3.93 (m, 1H), 4.94 (p, J=2.4 Hz, 2H), 7.38 (d, J=4.9 Hz, 1H), 7.42-7.57 (m, 4H), 7.89-7.92 (m, 3H), 8.18-8.21 (m, 2H), 8.27 (dd, J=8.6 Hz, 0.8 Hz, 1H), 8.53 (s, 1H).

Workup

  1. customThe excess POCl3 was removed under reduced pressure
  2. customthe residue was quenched with 2 N NH3 in isopropanol (250 mL) at 0° C.
  3. washThe aqueous layer was washed with DCM (100 mL×2)
  4. dry with materialthe combined organic layer was dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe crude product was purified by silica gel column chromatography (flash column)
  8. washeluting with 20-50% EtOAc in hexane
  9. concentrationConcentration in vacuo of the product-rich fractions

Sources & evidence

ORD record
ord-c38497de824b4492b0ddcdff4c5f7ee7
Source dataset
uspto-grants-2014_02
Patent number
US08653268B2

Reaction notes

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