Phosphorus oxychloride → HCID 11471056, compound

HRID 2373876Notes

Reaction equation

HRID 2373876 reaction equation
Cl[C:2]1[C:3]2[N:4]([C:8]([CH:17]3[CH2:20][CH2:19][CH2:18]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.ClC1C(C(NC(C2CCC2)=O)C2C=CC=CC=2)=[N:24]C=CN=1.O=P(Cl)(Cl)Cl>>[CH:17]1([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:24])[C:3]3=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:9]=2)[CH2:20][CH2:19][CH2:18]1

Participants

4

Reactant 3

HCID 24813Phosphorus oxychlorideHCID 59852761HCID 59852761, compoundHCID 59852780HCID 59852780, compound

Product 1

HCID 11471056HCID 11471056, compoundYield 90%

Conditions

Temperature
55 °C

Procedure

8-Chloro-3-cyclobutyl-1-phenylimidazo[1,5-a]pyrazine: A mixture of cyclobutanecarboxylic acid [(3-chloropyrazin-2-yl)-phenylmethyl]-amide (710 mg, 2.35 mmol) and POCl3 (15 mL, 25 g, 163 mmol) was heated to 55° C., under N2 atmosphere, for 21 h. POCl3 was evaporated in vacuo, a cold solution of NH3 in i-PrOH (2M, 15 mL) was added until pH was basic, and rotary evaporation was used to remove excess solvent. The crude material was suspended between EtOAc and dH2O, the layers were separated, and the aqueous layer was extracted with EtOAc (4×50 mL). The combined organic layers were washed with NaHCO3 sat. aq. sol. (2×50 mL) and brine (1×50 mL), dried over anhydrous MgSO4, and filtered. Sample was purified by filtration through a silica gel plug with 10% EtOAc:CH2Cl2 (250 mL) and filtrate was concentrated in vacuo, affording 602.9 mg (90%, 2.125 mmol) of the title compound, containing ≈0.5 equivalents of reduced DIAD and ≦0.06 equivalents of cyclobutanecarboxylic acid [(3-chloropyrazin-2-yl)-phenylmethyl]-amide (4), as a gold-colored solid; 1H NMR (CDCl3, 400 MHz) δ 2.00-2.11 (m, 1H), 2.13-2.26 (m, 1H), 2.47-2.57 (m, 2H), 2.60-2.72 (m, 2H), 3.85 (quint, J=8.4 Hz, 1H), 7.30 (d, J=5.2 Hz, 1H), 7.38-7.47 (m, 3H), 7.50 (d, J=5.2 Hz, 1H), 7.67-7.71 (m, 2H). MS (ES+): m/z 284.1/286.1 (100/55) [MH+].

Workup

  1. customPOCl3 was evaporated in vacuo
  2. additiona cold solution of NH3 in i-PrOH (2M, 15 mL) was added until pH
  3. customrotary evaporation
  4. customto remove excess solvent
  5. customthe layers were separated
  6. extractionthe aqueous layer was extracted with EtOAc (4×50 mL)
  7. washThe combined organic layers were washed with NaHCO3 sat. aq. sol. (2×50 mL) and brine (1×50 mL)
  8. dry with materialdried over anhydrous MgSO4
  9. filtrationfiltered
  10. filtrationSample was purified by filtration through a silica gel plug with 10% EtOAc
  11. concentrationCH2Cl2 (250 mL) and filtrate was concentrated in vacuo

Sources & evidence

ORD record
ord-897cdbb26adb4317bae5e033d0073ac8
Source dataset
uspto-grants-2008_12
Patent number
US07459554B2

Reaction notes

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