Phosphorus oxychloride → 7-(8-Chloro-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-quinoline

HRID 422615Notes

Reaction equation

HRID 422615 reaction equation
O=P(Cl)(Cl)Cl.[Cl:6][C:7]1[C:8]([CH:13]([NH:24][C:25]([CH:27]2[CH2:30][CH2:29][CH2:28]2)=O)[C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][CH:20]=[N:21]3)=[CH:16][CH:15]=2)=[N:9][CH:10]=[CH:11][N:12]=1>>[Cl:6][C:7]1[C:8]2[N:9]([C:25]([CH:27]3[CH2:30][CH2:29][CH2:28]3)=[N:24][C:13]=2[C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][CH:20]=[N:21]3)=[CH:16][CH:15]=2)[CH:10]=[CH:11][N:12]=1

Participants

3

Reactant 2

HCID 24813Phosphorus oxychlorideHCID 57680974N-[(3-chloro-2-pyrazinyl)-7-quinolinylmethyl]cyclobutanecarboxamide

Product 1

HCID 576808877-(8-Chloro-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-quinoline

Conditions

Temperature
70 °C

Procedure

A mixture of POCl3 (8 mL, 13 g, 87 mmol) and cyclobutanecarboxylic acid [(3-chloropyrazin-2-yl)-quinolin-7-ylmethyl]-amide (566 mg, 1.60 mmol) was heated to 55° C. for 21.5 h and to 70° C. for 6 h. POCl3 was evaporated, a cold solution of NH3 in iPrOH (2 M, 10 mL) was added, the suspension was filtered, and the solid was washed with iPrOH. The crude material contained in the combined filtrate and washings was adsorbed onto Hydromatrix and chromatographed on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with hexanes:EtOAc 1:1 (1-13)→1:3 (14-38)], yielding the title compound as a yellow foam; 1H NMR (CDCl3, 400 MHz) δ 2.05-2.14 (m, 1H), 2.16-2.28 (m, 1H), 2.50-2.60 (m, 2H), 2.63-2.75 (m, 2H), 3.89 (quint, J=8.4 Hz, 1H), 7.35 (d, J=4.4 Hz, 1H), 7.44 (dd, J=4.2, 8.2 Hz, 1H), 7.55 (d, J=5.2 Hz, 1H), 7.90 (d, J=8.4 Hz, 1H), 8.13 (dd, J=1.6, 8.4 Hz, 1H), 8.22 (d, J=8.2 Hz, 1H), 8.46 (s, 1H), 8.98 (dd, J=1.6, 4.2 Hz, 1H); MS (ES+): m/z 335.1/337.1 (100/44) [MH+].

Workup

  1. customPOCl3 was evaporated
  2. additiona cold solution of NH3 in iPrOH (2 M, 10 mL) was added
  3. filtrationthe suspension was filtered
  4. washthe solid was washed with iPrOH
  5. customchromatographed on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with hexanes:EtOAc 1:1 (1-13)→1:3 (14-38)]

Sources & evidence

ORD record
ord-758d79c84a8f48fc932104d29d8ca89e
Source dataset
uspto-grants-2012_01
Patent number
US08101613B2

Reaction notes

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