3-(8-Chloroimidazo[1,5-A]pyrazin-3-YL)cyclobutanone → 3-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol
Reaction equation
[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:14][C:13](=[O:15])[CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[CH3:16][Mg]Cl>C1COCC1>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:12][C:13]([CH3:16])([OH:15])[CH2:14]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1Participants
Conditions
- Temperature
- -78 °C
Procedure
3-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutanone (1.95 g, 8.80 mmol) in anhydrous THF (77.78 mL) at −78° C. under an atmosphere of nitrogen was treated slowly with a 3.0 M solution of methylmagnesium chloride in THF (5.9 mL). The solution stirred for 3 hr at −78° C. then quenched with 40 mL of semi-saturated aqueous NH4Cl (NH4Cl dilution in 1:1 mixture with water) at −78° C. and allowed to warm up to rt. The mixture was then extracted with EtOAc (3×40 mL) and the combined extracts washed with brine (30 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude solid was purified by chromatography over silica gel eluting with 1:1 EtOAc/DCM to 4% MeOH in (1:1) EtOAc/DCM to afford desired product. 1H-NMR (400 MHz, CDCl3) δ ppm 1.54 (s, 3 H), 2.74-2.60 (m, 4 H), 3.75-3.39 (m, 1 H), 7.35 (d, J=5.04 Hz, 1 H), 7.71 (d, J=5.00 Hz, 1 H) and 7.86 (s, 1 H). MS (ES+): m/z 238.15 and 240.17 [MH+].
Workup
- customthen quenched with 40 mL of semi-saturated aqueous NH4Cl (NH4Cl dilution in 1:1 mixture with water) at −78° C.
- temperatureto warm up to rt
- extractionThe mixture was then extracted with EtOAc (3×40 mL)
- washthe combined extracts washed with brine (30 mL)
- dry with materialdried over magnesium sulfate
- filtrationfiltered
- concentrationconcentrated in vacuo
- customThe crude solid was purified by chromatography over silica gel eluting with 1:1 EtOAc/DCM to 4% MeOH in (1:1) EtOAc/DCM
Sources & evidence
- ORD record
- ord-36d290dad2404a418fcd7cb2d1e51e0b
- Source dataset
- uspto-grants-2012_02
- Patent number
- US08114846B2
Reaction notes
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