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

HRID 2402634Notes

Reaction equation

HRID 2402634 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)C=O.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

N-[(3-Chloropyrazin-2-yl)methyl]-3-methylenecyclobutanecarboxamide (52.1 g, 219.2 mmol) in anhydrous MeCN (1.0 L) was treated with DMF (1.0 mL) and POCl3 (100 mL, 1.09 mol) and the mixture was stirred at 55° C. for 30 min. under a gentle stream of N2. The reaction was then concentrated in vacuo and the residue reconstituted in CH2Cl2 and treated with cold 2.0 M NH3 in IPA. This mixture was concentrated in vacuo, water added to dissolve the salts, and then extracted with CH2Cl2 (4×60 mL). The organic layers where combined and washed with sat. NaHCO3 (1×70 mL) dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by chromatography over silica gel eluting with 2:1 hexane:EtOAc to yield desired product. 1H NMR (400 MHz, CDCl3) δ ppm 3.24-3.30 (4H, m), 3.78-3.85 (1H, m), 4.89-4.94 (2H, m), 7.33 (1H, d, J-4.99 Hz), 7.53 (1H, d, J=5.09 Hz) and 7.82 (1H, s). MS (ES+): m/z 220.28 and 222.30 [MH+].

Workup

  1. concentrationThe reaction was then concentrated in vacuo
  2. additiontreated with cold 2.0 M NH3 in IPA
  3. concentrationThis mixture was concentrated in vacuo, water
  4. additionadded
  5. dissolutionto dissolve the salts
  6. extractionextracted with CH2Cl2 (4×60 mL)
  7. washwashed with sat. NaHCO3 (1×70 mL)
  8. dry with materialdried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customThe crude material was purified by chromatography over silica gel eluting with 2:1 hexane

Sources & evidence

ORD record
ord-da2bf8d1298a496492608074f6631010
Source dataset
uspto-grants-2014_08
Patent number
US08796455B2

Reaction notes

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