Nitrogen → 8-Chloro-3-(3-methylenecyclobutyl)imidazo[1,5-a]pyrazine

HRID 1878835Notes

Reaction equation

HRID 1878835 reaction equation
[Cl:1][C:2]1[C:3]([CH2:8][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.N#N>CC#N>[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][CH:8]=2)[CH:5]=[CH:6][N:7]=1

Participants

6

Reactant 4

HCID 947NitrogenHCID 6228DimethylformamideHCID 24813Phosphorus oxychlorideHCID 57681076N-((3-chloropyrazin-2-yl)methyl)-3-methylenecyclobutanecarboxamide

Product 1

HCID 576810508-Chloro-3-(3-methylenecyclobutyl)imidazo[1,5-a]pyrazine

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

3-Methylene-cyclobutanecarboxylic acid (3-chloro-pyrazin-2-ylmethyl)-amide (52.1 g, 219.2 mmol) was dissolved in 1.0 L of anhydrous MeCN. Followed by the addition of DMF (1.0 mL) and POCl3 (100 mL, 1.09 mol). The reaction was heated to 55° C. for 30 min. with a slow N2 bubbling the reaction. The reaction was then concentrated in vacuo, basified with cold 2.0M NH3 in IPA with CH2Cl2. The IPA/CH2Cl2 was concentrated in vacuo and the salts were dissolved with minimal water and extracted with CH2Cl2 (4×). The organic layers where combined and washed with sat. NaHCO3 (1×), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified via silica gel column chromatography [eluting with 2:1 Hex:EtOAc] to yield the title compound as a light yellow solid; 1H NMR (400 MHz, CDCl3) δ 3.24-3.30 (4 H, m), 3.78-3.85 (1 H, m), 4.89-4.94 (2 H, m), 7.33 (1 H, d, J=4.99 Hz), 7.53 (1 H, d, J=5.09 Hz), 7.82 (1 H, s); MS (ES+): m/z 220.28/222.30 (100/80) [MH+]; HPLC: tR=2.87 min (OpenLynx, polar—5 min).

Workup

  1. customthe reaction
  2. concentrationThe reaction was then concentrated in vacuo
  3. concentrationThe IPA/CH2Cl2 was concentrated in vacuo
  4. dissolutionthe salts were dissolved with minimal water
  5. extractionextracted with CH2Cl2 (4×)
  6. washwashed with sat. NaHCO3 (1×)
  7. dry with materialdried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customThe crude product was purified via silica gel column chromatography [eluting with 2:1 Hex:EtOAc]

Sources & evidence

ORD record
ord-162ee5515b88406eb10215d08ce9a8e5
Source dataset
uspto-grants-2012_11
Patent number
US08314111B2

Reaction notes

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